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Blair AB, Zheng L, Soares KC. The Landmark Series: Therapeutic Cancer Vaccine Strategies for Cold Tumors. Ann Surg Oncol 2025:10.1245/s10434-025-17281-1. [PMID: 40325301 DOI: 10.1245/s10434-025-17281-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 05/07/2025]
Abstract
Immunologically cold tumors present a significant challenge in cancer treatment due to their limited baseline immune infiltration and resistance to immunotherapy. Cancer vaccines offer a promising strategy to overcome this barrier by introducing high-quality, tumor-relevant antigens that can stimulate an effective anti-tumor immune response. Therapeutic cancer vaccines are being explored in the neoadjuvant, adjuvant, and minimal residual disease contexts to enhance immune activation and promote immune cell infiltration and function, with the goal to eradicate malignant cells and improve patient survival. Critical hurdles remain in optimizing antigen selection, determining the most effective vaccine formulations, and defining the ideal clinical setting for vaccine use. Moreover, rational combinations of cancer vaccines with other immune modulators (e.g., adjuvants, immune checkpoint inhibitors, and cytokines) may hold the key to enhancing vaccine efficacy and expanding therapeutic options for difficult-to-treat malignancies. This review examines current advancements in cancer vaccines and their utilization for immunologically cold tumors in the perioperative setting, highlighting ongoing challenges and future directions in this evolving field.
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Affiliation(s)
- Alex B Blair
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Lei Zheng
- Mays Cancer Center at the University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, TX, USA
- Department of Oncology and Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kevin C Soares
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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2
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Liang KL, Azad NS. Immune-Based Strategies for Pancreatic Cancer in the Adjuvant Setting. Cancers (Basel) 2025; 17:1246. [PMID: 40227779 PMCID: PMC11988091 DOI: 10.3390/cancers17071246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation of immune-based strategies in the adjuvant setting remains an area of intense investigation with unrealized promise. It offers the potential of providing durable disease control for micro-metastatic disease following curative intent surgery and enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, most of these attempts have failed to demonstrate significant clinical success, likely due to the immunosuppressive tumor microenvironment (TME) and individual genetic heterogeneity. Despite these challenges, immune-based strategies, such as therapeutic vaccines targeted towards neoantigens, have demonstrated promise via immune activation and induction of T-cell tumor infiltration. In this review, we will highlight the foundational lessons learned from previous clinical trials of adjuvant immunotherapy, discussing the knowledge gained from analyses of trials with disappointing results. In addition, we will discuss how these data have been incorporated to design new agents and study concepts that are proving to be exciting in more recent trials, such as shared antigen vaccines and combination therapy with immune-checkpoint inhibitors and chemotherapy. This review will evaluate novel approaches in ongoing and future clinical studies and provide insight into how these immune-based strategies might evolve to address the unique challenges for treatment of PDAC in the adjuvant setting.
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Affiliation(s)
| | - Nilofer S. Azad
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
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3
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Delgado-Almenta V, Blaya-Cánovas JL, Calahorra J, López-Tejada A, Griñán-Lisón C, Granados-Principal S. Cancer Vaccines and Beyond: The Transformative Role of Nanotechnology in Immunotherapy. Pharmaceutics 2025; 17:216. [PMID: 40006583 PMCID: PMC11859086 DOI: 10.3390/pharmaceutics17020216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/20/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality globally, responsible for approximately 10 million deaths in 2022 and an estimated 21 million new cases in 2024. Traditional cancer treatments such as surgery, radiation therapy, and chemotherapy often present limitations in efficacy and side effects. However, immunotherapeutic vaccines have emerged as a promising approach, leveraging the body's immune system to target and eliminate cancer cells. This review examines the evolving landscape of cancer vaccines, differentiating between preventive and therapeutic strategies and highlighting the significance of tumor-specific antigens, including tumor-associated antigens (TAAs) and neoantigens. Recent advancements in vaccine technology, particularly through nanotechnology, have resulted in the development of nanovaccines, which enhance antigen stability, optimize delivery to immune cells, and promote robust immune responses. Notably, clinical data indicate that patients receiving immune checkpoint inhibitors can achieve overall survival rates of approximately 34.8 months compared to just 15.7 months for traditional therapies. Despite these advancements, challenges remain, such as the immunosuppressive tumor microenvironment and tumor heterogeneity. Emerging evidence suggests that combining nanovaccines with immunomodulators may enhance therapeutic efficacy by overcoming these obstacles. Continued research and interdisciplinary collaboration will be essential to fully exploit the promise of nanovaccines, ultimately leading to more effective and accessible treatments for cancer patients. The future of cancer immunotherapy appears increasingly hopeful as these innovative strategies pave the way for enhanced patient outcomes and an improved quality of life in oncology.
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Affiliation(s)
- Violeta Delgado-Almenta
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
| | - Jose L. Blaya-Cánovas
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Jesús Calahorra
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Araceli López-Tejada
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18011 Granada, Spain
| | - Carmen Griñán-Lisón
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18011 Granada, Spain
- Excellence Research Unit “Modeling Nature” (MNat), Centro de Investigación Biomédica (CIBM), University of Granada, 18016 Granada, Spain
| | - Sergio Granados-Principal
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain; (V.D.-A.); (J.L.B.-C.); (J.C.); (A.L.-T.)
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18011 Granada, Spain
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4
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Hoang T, Tsang ES. Advances in Novel Targeted Therapies for Pancreatic Adenocarcinoma. J Gastrointest Cancer 2025; 56:38. [PMID: 39762686 DOI: 10.1007/s12029-024-01149-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. Recent advances in targeted therapies have opened new avenues for intervention in PDAC, focusing on key genetic and molecular pathways that drive tumor progression. METHODS In this review, we provide an overview on advances in novel targeted therapies in pancreatic adenocarcinoma. RESULTS Here, we explore the latest development in targeting the KRAS pathway, a historically "undruggable" target crucial to PDAC pathogenesis. Strategies to inhibit KRAS include direct KRAS-targeted therapies, modulation of upstream and downstream signaling, KRAS-specific siRNA, and novel combination therapies integrating KRAS inhibitors with immune checkpoint blockade, PARP inhibitors, chemotherapy, CDK4/6 inhibitors, and autophagy modulators. Beyond KRAS, emerging targets such as NRG1 fusions, NTRK/ROS1 fusions, RET alterations, and the PRMT5/CDKN2A/MAT2A axis, along with EGFR and Claudin18.2 inhibitors, are also discussed as promising therapeutic strategies. Additionally, the review highlights novel approaches for microsatellite instability-high (MSIH) PDAC and emerging therapies, including adoptive cell therapies (CAR-T, TCR, TIL), cancer vaccines, and strategies to modify the tumor microenvironment. CONCLUSION Overall, the rapid evolution of targeted therapies offers renewed optimism in the fight against pancreatic cancer, a malignancy with historically poor outcomes.
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Affiliation(s)
- Tuan Hoang
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Erica S Tsang
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
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5
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Beatty GL, Jaffee EM. Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer. Carcinogenesis 2024; 45:826-835. [PMID: 39514560 PMCID: PMC11584293 DOI: 10.1093/carcin/bgae065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/16/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease for which remarkable therapeutic resistance is the norm. Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a remarkably immunosuppressive tumor microenvironment (TME) and systemic inflammation. This review discusses the potential of both exogenous and in situ vaccination strategies to overcome these barriers and enhance anti-tumor immunity in PDA. Exogenous vaccines, including whole-cell, dendritic cell, peptide, and nucleic acid-based vaccines, have shown varying degrees of promise but face challenges related to antigen selection, production complexities, and patient-specific factors. In contrast, in situ vaccination strategies leverage conventional cytotoxic therapies, such as chemotherapy and radiation therapy, to induce immunogenic cell death and modulate the TME with the aim to stimulate anti-tumor immunity. While preclinical studies support the use of in situ vaccination, balancing the stimulatory and inhibitory effects is likely fundamental to eliciting productive anti-tumor responses in patients. Ongoing research seeks to identify new innovative strategies that can harness the endogenous immune response and trigger in situ vaccination. Overall, while both vaccination approaches offer significant potential, further research and clinical trials will be needed to optimize these strategies for improving patient outcomes in PDA.
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Affiliation(s)
- Gregory L Beatty
- Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, 3400 Civic Center Blvd, South Pavilion, Rm 8-107, Philadelphia, PA 19104, United States
| | - Elizabeth M Jaffee
- The Sidney Kimmel Comprehensive Cancer Center, The Bloomberg Kimmel Institute for Immunotherapy, The Cancer Convergence Institute, Johns Hopkins University School of Medicine, 4M07 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21287, United States
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6
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Wang J, Yang J, Narang A, He J, Wolfgang C, Li K, Zheng L. Consensus, debate, and prospective on pancreatic cancer treatments. J Hematol Oncol 2024; 17:92. [PMID: 39390609 PMCID: PMC11468220 DOI: 10.1186/s13045-024-01613-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/25/2024] [Indexed: 10/12/2024] Open
Abstract
Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.
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Affiliation(s)
- Junke Wang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jie Yang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Amol Narang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jin He
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Christopher Wolfgang
- Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY, USA
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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7
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Amhis N, Carignan J, Tai LH. Transforming pancreaticobiliary cancer treatment: Exploring the frontiers of adoptive cell therapy and cancer vaccines. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200825. [PMID: 39006944 PMCID: PMC11246060 DOI: 10.1016/j.omton.2024.200825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Pancreaticobiliary cancer, encompassing malignancies of both the pancreatic and biliary tract, presents a formidable clinical challenge marked by a uniformly bleak prognosis. The asymptomatic nature of its early stages often leads to delayed detection, contributing to an unfavorable 5-year overall survival rate. Conventional treatment modalities have shown limited efficacy, underscoring the urgent need for alternative therapeutic approaches. In recent years, immunotherapy has emerged as a promising avenue in the fight against pancreaticobiliary cancer. Strategies such as therapeutic vaccines and the use of tumor-infiltrating lymphocytes have garnered attention for their potential to elicit more robust and durable responses. This review seeks to illuminate the landscape of emerging immunotherapeutic interventions, offering insights from both clinical and research perspectives. By deepening our understanding of pancreaticobiliary cancer and exploring innovative treatment modalities, we aim to catalyze improvements in patient outcomes and quality of life.
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Affiliation(s)
- Nawal Amhis
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Department of Surgery, Division of General Surgery, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Julie Carignan
- Centre de Recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada
| | - Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada
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8
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Brugiapaglia S, Spagnolo F, Intonti S, Novelli F, Curcio C. Fighting Pancreatic Cancer with a Vaccine-Based Winning Combination: Hope or Reality? Cells 2024; 13:1558. [PMID: 39329742 PMCID: PMC11430323 DOI: 10.3390/cells13181558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/06/2024] [Accepted: 09/15/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic adenocarcinoma (PDA) represents the fourth leading cause of cancer-related mortality in the USA. Only 20% of patients present surgically resectable and potentially curable tumors at diagnosis, while 80% are destined for poor survival and palliative chemotherapy. Accordingly, the advancement of innovative and effective therapeutic strategies represents a pivotal medical imperative. It has been demonstrated that targeting the immune system represents an effective approach against several solid tumors. The immunotherapy approach encompasses a range of strategies, including the administration of antibodies targeting checkpoint molecules (immune checkpoint inhibitors, ICIs) to disrupt tumor suppression mechanisms and active immunization approaches that aim to stimulate the host's immune system. While vaccines have proved effective against infectious agents, vaccines for cancer remain an unfulfilled promise. Vaccine-based therapy targeting tumor antigens has the potential to be a highly effective strategy for initiating and maintaining T cell recognition, enhancing the immune response, and ultimately promoting cancer treatment success. In this review, we examined the most recent clinical trials that employed diverse vaccine types to stimulate PDA patients' immune systems, either independently or in combination with chemotherapy, radiotherapy, ICIs, and monoclonal antibodies with the aim of ameliorating PDA patients' quality of life and extend their survival.
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Affiliation(s)
- Silvia Brugiapaglia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44bis, 10126 Turin, Italy; (S.B.); (S.I.); (F.N.)
| | - Ferdinando Spagnolo
- School of Advanced Defence Studies, Defence Research & Analysis Institute, Piazza della Rovere 83, 00165 Rome, Italy; (F.S.)
| | - Simona Intonti
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44bis, 10126 Turin, Italy; (S.B.); (S.I.); (F.N.)
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44bis, 10126 Turin, Italy; (S.B.); (S.I.); (F.N.)
| | - Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44bis, 10126 Turin, Italy; (S.B.); (S.I.); (F.N.)
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9
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Phan T, Fan D, Melstrom LG. Developing Vaccines in Pancreatic Adenocarcinoma: Trials and Tribulations. Curr Oncol 2024; 31:4855-4884. [PMID: 39329989 PMCID: PMC11430674 DOI: 10.3390/curroncol31090361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic adenocarcinoma represents one of the most challenging malignancies to treat, with dismal survival rates despite advances in therapeutic modalities. Immunotherapy, particularly vaccines, has emerged as a promising strategy to harness the body's immune system in combating this aggressive cancer. This abstract reviews the trials and tribulations encountered in the development of vaccines targeting pancreatic adenocarcinoma. Key challenges include the immunosuppressive tumor microenvironment, the heterogeneity of tumor antigens, and a limited understanding of immune evasion mechanisms employed by pancreatic cancer cells. Various vaccine platforms, including peptide-based, dendritic cell-based, and viral vector-based vaccines, have been explored in preclinical and clinical settings. However, translating promising results from preclinical models to clinical efficacy has proven elusive. In recent years, mRNA vaccines have emerged as a promising immunotherapeutic strategy in the fight against various cancers, including pancreatic adenocarcinoma. We will discuss the potential applications, opportunities, and challenges associated with mRNA vaccines in pancreatic cancer treatment.
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Affiliation(s)
- Thuy Phan
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Darrell Fan
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Laleh G. Melstrom
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA;
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10
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Brugiapaglia S, Bulfamante S, Curcio C, Arigoni M, Calogero R, Bonello L, Genuardi E, Spadi R, Satolli MA, Campra D, Giordano D, Cappello P, Cordero F, Novelli F. In pancreatic cancer patients, chemotherapy reshapes the gene expression profile and antigen receptor repertoire of T lymphocytes and enhances their effector response to tumor-associated antigens. Front Immunol 2024; 15:1427424. [PMID: 39176093 PMCID: PMC11339620 DOI: 10.3389/fimmu.2024.1427424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 07/15/2024] [Indexed: 08/24/2024] Open
Abstract
Introduction Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy. Methods Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT. Results CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature. Conclusion These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT.
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MESH Headings
- Humans
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/therapy
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Male
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/genetics
- Carcinoma, Pancreatic Ductal/therapy
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/drug therapy
- Female
- Transcriptome
- Aged
- Middle Aged
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Gene Expression Regulation, Neoplastic
- Gene Expression Profiling
- Phosphopyruvate Hydratase/genetics
- Phosphopyruvate Hydratase/immunology
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
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Affiliation(s)
- Silvia Brugiapaglia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
| | - Maddalena Arigoni
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Raffaele Calogero
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Lisa Bonello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Elisa Genuardi
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Rosella Spadi
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Maria Antonietta Satolli
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Donata Campra
- Struttura Complessa (SC) Chirurgia generale d’urgenza e pronto soccorso, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Daniele Giordano
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
| | | | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
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11
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Liu R, Li J, Liu L, Wang W, Jia J. Tumor-associated macrophages (TAMs): Constructing an immunosuppressive microenvironment bridge for pancreatic ductal adenocarcinoma (PDAC). CANCER PATHOGENESIS AND THERAPY 2024. [DOI: 10.1016/j.cpt.2024.07.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/19/2025]
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12
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Farhangnia P, Khorramdelazad H, Nickho H, Delbandi AA. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J Hematol Oncol 2024; 17:40. [PMID: 38835055 PMCID: PMC11151541 DOI: 10.1186/s13045-024-01561-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024] Open
Abstract
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
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Affiliation(s)
- Pooya Farhangnia
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Nickho
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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13
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Sussman TA, Severgnini M, Giobbie-Hurder A, Friedlander P, Swanson SJ, Jaklitsch M, Clancy T, Goguen LA, Lautz D, Swanson R, Daley H, Ritz J, Dranoff G, Hodi FS. Phase II trial of vaccination with autologous, irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor in patients with stage III and IV melanoma. Front Oncol 2024; 14:1395978. [PMID: 38812776 PMCID: PMC11133610 DOI: 10.3389/fonc.2024.1395978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/16/2024] [Indexed: 05/31/2024] Open
Abstract
Background In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). The safety, efficacy and anti-tumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation. Methods In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x106, 4x106, or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients. Results GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit. Conclusions Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed.
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Affiliation(s)
- Tamara A. Sussman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Mariano Severgnini
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Clinical Sciences, Curis, Inc., Lexington, MA, United States
| | - Anita Giobbie-Hurder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Division of Biostatistics, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Philip Friedlander
- Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott J. Swanson
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Michael Jaklitsch
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Thomas Clancy
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Laura A. Goguen
- Division of Otolaryngology, Brigham and Women’s Hospital, Boston, MA, United States
| | - David Lautz
- Department of Surgery, Emerson Hospital, Concord, MA, United States
| | - Richard Swanson
- Department of Surgery, UMass Chan Medical School, Worcester, MA, United States
| | - Heather Daley
- Connell and O’Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Jerome Ritz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Connell and O’Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Glenn Dranoff
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - F. Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medical Oncology, Parker Institute for Cancer Immunotherapy, Dana-Farber Cancer Institute, Boston, MA, United States
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14
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Song J, Zhang Y, Zhou C, Zhan J, Cheng X, Huang H, Mao S, Zong Z. The dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy. Int Immunopharmacol 2024; 132:112037. [PMID: 38599100 DOI: 10.1016/j.intimp.2024.112037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/24/2024] [Accepted: 04/05/2024] [Indexed: 04/12/2024]
Abstract
Colorectal cancer (CRC) is a typical cancer that accounts for 10% of all new cancer cases annually and nearly 10% of all cancer deaths. Despite significant progress in current classical interventions for CRC, these traditional strategies could be invasive and with numerous adverse effects. The poor prognosis of CRC patients highlights the evident and pressing need for more efficient and targeted treatment. Novel strategies regarding mRNA vaccines for anti-tumor therapy have also been well-developed since the successful application for the prevention of COVID-19. mRNA vaccine technology won the 2023 Nobel Prize in Physiology or Medicine, signaling a new direction in human anti-cancer treatment: mRNA medicine. As a promising new immunotherapy in CRC and other multiple cancer treatments, the mRNA vaccine has higher specificity, better efficacy, and fewer side effects than traditional strategies. The present review outlines the basics of mRNA vaccines and their advantages over other vaccines and informs an available strategy for developing efficient mRNA vaccines for CRC precise treatment. In the future, more exploration of mRNA vaccines for CRC shall be attached, fostering innovation to address existing limitations.
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Affiliation(s)
- Jingjing Song
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; School of Ophthalmology and Optometry, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Yujun Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; Huankui Academy, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Chulin Zhou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China; The Second Clinical Medical College, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Jianhao Zhan
- Huankui Academy, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Haoyu Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China
| | - Shengxun Mao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China.
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang 330006, Jiangxi, China.
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15
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Zheng R, Liu X, Zhang Y, Liu Y, Wang Y, Guo S, Jin X, Zhang J, Guan Y, Liu Y. Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application. Front Immunol 2024; 15:1383978. [PMID: 38756774 PMCID: PMC11096556 DOI: 10.3389/fimmu.2024.1383978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Pancreatic cancer is a highly aggressive malignant tumor, that is becoming increasingly common in recent years. Despite advances in intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted therapy, the overall survival rate has not significantly improved in patients with pancreatic cancer. This may be attributed to the insidious onset, unknown pathophysiology, and poor prognosis of the disease. It is therefore essential to identify and develop more effective and safer treatments for pancreatic cancer. Tumor immunotherapy is the new and fourth pillar of anti-tumor therapy after surgery, radiotherapy, and chemotherapy. Significant progress has made in the use of immunotherapy for a wide variety of malignant tumors in recent years; a breakthrough has also been made in the treatment of pancreatic cancer. This review describes the advances in immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus, and matrix-depletion therapies for the treatment of pancreatic cancer. At the same time, some new potential biomarkers and potential immunotherapy combinations for pancreatic cancer are discussed. The molecular mechanisms of various immunotherapies have also been elucidated, and their clinical applications have been highlighted. The current challenges associated with immunotherapy and proposed strategies that hold promise in overcoming these limitations have also been discussed, with the aim of offering new insights into immunotherapy for pancreatic cancer.
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Affiliation(s)
- Rui Zheng
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaobin Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Yongxian Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yaping Wang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Shutong Guo
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaoyan Jin
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Jing Zhang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yuehong Guan
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yusi Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
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16
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Pourali G, Kazemi D, Chadeganipour AS, Arastonejad M, Kashani SN, Pourali R, Maftooh M, Akbarzade H, Fiuji H, Hassanian SM, Ghayour-Mobarhan M, Ferns GA, Khazaei M, Avan A. Microbiome as a biomarker and therapeutic target in pancreatic cancer. BMC Microbiol 2024; 24:16. [PMID: 38183010 PMCID: PMC10768369 DOI: 10.1186/s12866-023-03166-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 12/18/2023] [Indexed: 01/07/2024] Open
Abstract
Studying the effects of the microbiome on the development of different types of cancer has recently received increasing research attention. In this context, the microbial content of organs of the gastrointestinal tract has been proposed to play a potential role in the development of pancreatic cancer (PC). Proposed mechanisms for the pathogenesis of PC include persistent inflammation caused by microbiota leading to an impairment of antitumor immune surveillance and altered cellular processes in the tumor microenvironment. The limited available diagnostic markers that can currently be used for screening suggest the importance of microbial composition as a non-invasive biomarker that can be used in clinical settings. Samples including saliva, stool, and blood can be analyzed by 16 s rRNA sequencing to determine the relative abundance of specific bacteria. Studies have shown the potentially beneficial effects of prebiotics, probiotics, antibiotics, fecal microbial transplantation, and bacteriophage therapy in altering microbial diversity, and subsequently improving treatment outcomes. In this review, we summarize the potential impact of the microbiome in the pathogenesis of PC, and the role these microorganisms might play as biomarkers in the diagnosis and determining the prognosis of patients. We also discuss novel treatment methods being used to minimize or prevent the progression of dysbiosis by modulating the microbial composition. Emerging evidence is supportive of applying these findings to improve current therapeutic strategies employed in the treatment of PC.
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Affiliation(s)
- Ghazaleh Pourali
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Danial Kazemi
- Student Research Committee, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan, Iran
| | | | - Mahshid Arastonejad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Roozbeh Pourali
- Student Research Committee, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mina Maftooh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Akbarzade
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Fiuji
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq.
- School of Mechanical, Medical and Process Engineering, Science and Engineering Faculty, Queensland University of Technology, 2 George St, Brisbane City, QLD, 4000, Australia.
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17
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Johnson JA, Stein-O’Brien GL, Booth M, Heiland R, Kurtoglu F, Bergman DR, Bucher E, Deshpande A, Forjaz A, Getz M, Godet I, Lyman M, Metzcar J, Mitchell J, Raddatz A, Rocha H, Solorzano J, Sundus A, Wang Y, Gilkes D, Kagohara LT, Kiemen AL, Thompson ED, Wirtz D, Wu PH, Zaidi N, Zheng L, Zimmerman JW, Jaffee EM, Hwan Chang Y, Coussens LM, Gray JW, Heiser LM, Fertig EJ, Macklin P. Digitize your Biology! Modeling multicellular systems through interpretable cell behavior. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.17.557982. [PMID: 37745323 PMCID: PMC10516032 DOI: 10.1101/2023.09.17.557982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Cells are fundamental units of life, constantly interacting and evolving as dynamical systems. While recent spatial multi-omics can quantitate individual cells' characteristics and regulatory programs, forecasting their evolution ultimately requires mathematical modeling. We develop a conceptual framework-a cell behavior hypothesis grammar-that uses natural language statements (cell rules) to create mathematical models. This allows us to systematically integrate biological knowledge and multi-omics data to make them computable. We can then perform virtual "thought experiments" that challenge and extend our understanding of multicellular systems, and ultimately generate new testable hypotheses. In this paper, we motivate and describe the grammar, provide a reference implementation, and demonstrate its potential through a series of examples in tumor biology and immunotherapy. Altogether, this approach provides a bridge between biological, clinical, and systems biology researchers for mathematical modeling of biological systems at scale, allowing the community to extrapolate from single-cell characterization to emergent multicellular behavior.
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Affiliation(s)
- Jeanette A.I. Johnson
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Genevieve L. Stein-O’Brien
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
- Department of Neuroscience, Johns Hopkins University. Baltimore, MD USA
| | - Max Booth
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
| | - Randy Heiland
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Furkan Kurtoglu
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Daniel R. Bergman
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Elmar Bucher
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Atul Deshpande
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - André Forjaz
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University. Baltimore, MD USA
| | - Michael Getz
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Ines Godet
- Memorial Sloan Kettering Cancer Center. New York, NY USA
| | - Melissa Lyman
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - John Metzcar
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
- Department of Informatics, Indiana University. Bloomington, IN USA
| | - Jacob Mitchell
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
- Department of Human Genetics, Johns Hopkins University. Baltimore, MD USA
| | - Andrew Raddatz
- Department of Biomedical Engineering, Georgia Institute of Technology, Emory University. Atlanta, GA USA
| | - Heber Rocha
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Jacobo Solorzano
- Centre de Recherches en Cancerologie de Toulouse. Toulouse, France
| | - Aneequa Sundus
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Yafei Wang
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
| | - Danielle Gilkes
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
| | - Luciane T. Kagohara
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Ashley L. Kiemen
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
- Department of Pathology, Johns Hopkins University. Baltimore, MD USA
| | | | - Denis Wirtz
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University. Baltimore, MD USA
- Department of Pathology, Johns Hopkins University. Baltimore, MD USA
- Department of Materials Science and Engineering, Johns Hopkins University. Baltimore, MD USA
| | - Pei-Hsun Wu
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University. Baltimore, MD USA
| | - Neeha Zaidi
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Lei Zheng
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Jacquelyn W. Zimmerman
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Elizabeth M. Jaffee
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
| | - Young Hwan Chang
- Department of Biomedical Engineering, Oregon Health & Science University. Portland, OR USA
| | - Lisa M. Coussens
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University. Portland, OR USA
| | - Joe W. Gray
- Department of Biomedical Engineering, Oregon Health & Science University. Portland, OR USA
| | - Laura M. Heiser
- Department of Biomedical Engineering, Oregon Health & Science University. Portland, OR USA
| | - Elana J. Fertig
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Baltimore, MD USA
- Convergence Institute, Johns Hopkins University. Baltimore, MD USA
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University. Baltimore, MD USA
| | - Paul Macklin
- Department of Intelligent Systems Engineering, Indiana University. Bloomington, IN USA
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18
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Leowattana W, Leowattana P, Leowattana T. Systemic treatment for advanced pancreatic cancer. World J Gastrointest Oncol 2023; 15:1691-1705. [PMID: 37969416 PMCID: PMC10631439 DOI: 10.4251/wjgo.v15.i10.1691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/24/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023] Open
Abstract
Pancreatic cancer is a deadly disease with an extremely poor 5-year survival rate due to treatment resistance and late-stage detection. Despite numerous years of research and pharmaceutical development, these figures have not changed. Treatment options for advanced pancreatic cancer are still limited. This illness is typically detected at a late stage, making curative surgical resection impossible. Chemotherapy is the most commonly utilized technique for treating advanced pancreatic cancer but has poor efficacy. Targeted therapy and immunotherapy have made significant progress in many other cancer types and have been proven to have extremely promising possibilities; these therapies also hold promise for pancreatic cancer. There is an urgent need for research into targeted treatment, immunotherapy, and cancer vaccines. In this review, we emphasize the foundational findings that have fueled the therapeutic strategy for advanced pancreatic cancer. We also address current advancements in targeted therapy, immunotherapy, and cancer vaccines, all of which continue to improve the clinical outcome of advanced pancreatic cancer. We believe that clinical translation of these novel treatments will improve the low survival rate of this deadly disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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19
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Herpels M, Ishihara J, Sadanandam A. The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities. J Pathol 2023; 260:533-550. [PMID: 37550956 DOI: 10.1002/path.6171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 08/09/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi-faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer-associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Melanie Herpels
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Bioengineering, Imperial College London, London, UK
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, UK
| | - Anguraj Sadanandam
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Global Oncology, Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Translational Immunotherapy, Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
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20
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Heumann T, Judkins C, Li K, Lim SJ, Hoare J, Parkinson R, Cao H, Zhang T, Gai J, Celiker B, Zhu Q, McPhaul T, Durham J, Purtell K, Klein R, Laheru D, De Jesus-Acosta A, Le DT, Narang A, Anders R, Burkhart R, Burns W, Soares K, Wolfgang C, Thompson E, Jaffee E, Wang H, He J, Zheng L. A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. Nat Commun 2023; 14:3650. [PMID: 37339979 PMCID: PMC10281953 DOI: 10.1038/s41467-023-39196-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 06/01/2023] [Indexed: 06/22/2023] Open
Abstract
A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
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Affiliation(s)
- Thatcher Heumann
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, TN, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Carol Judkins
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Su Jin Lim
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Quantitative Sciences, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jessica Hoare
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Rose Parkinson
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Haihui Cao
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Tengyi Zhang
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
| | - Jessica Gai
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
| | - Betul Celiker
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Qingfeng Zhu
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas McPhaul
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jennifer Durham
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Katrina Purtell
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
| | - Rachel Klein
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel Laheru
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
| | - Ana De Jesus-Acosta
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
| | - Dung T Le
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
| | - Amol Narang
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert Anders
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Richard Burkhart
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William Burns
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kevin Soares
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Christopher Wolfgang
- Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY, USA
| | - Elizabeth Thompson
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth Jaffee
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hao Wang
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- Division of Quantitative Sciences, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jin He
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Cancer Convergence Institute and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program at Johns Hopkins, Baltimore, MD, USA.
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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21
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Dillman RO, Nistor GI, Keirstead HS. Autologous dendritic cells loaded with antigens from self-renewing autologous tumor cells as patient-specific therapeutic cancer vaccines. Hum Vaccin Immunother 2023:2198467. [PMID: 37133853 DOI: 10.1080/21645515.2023.2198467] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2023] Open
Abstract
A promising personal immunotherapy is autologous dendritic cells (DC) loaded ex vivo with autologous tumor antigens (ATA) derived from self-renewing autologous cancer cells. DC-ATA are suspended in granulocyte-macrophage colony stimulating factor at the time of each subcutaneous injection. Previously, irradiated autologous tumor cell vaccines have produced encouraging results in 150 cancer patients, but the DC-ATA vaccine demonstrated superiority in single-arm and randomized trials in metastatic melanoma. DC-ATA have been injected into more than 200 patients with melanoma, glioblastoma, and ovarian, hepatocellular, and renal cell cancers. Key observations include: [1] greater than 95% success rates for tumor cell cultures and monocyte collection for dendritic cell production; [2] injections are well-tolerated; [3] the immune response is rapid and includes primarily TH1/TH17 cellular responses; [4] efficacy has been suggested by delayed but durable complete tumor regressions in patients with measurable disease, by progression-free survival in glioblastoma, and by overall survival in melanoma.
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Affiliation(s)
| | - Gabriel I Nistor
- Research and Development, AIVITA Biomedical Inc, Irvine, CA, USA
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22
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de Scordilli M, Michelotti A, Zara D, Palmero L, Alberti M, Noto C, Totaro F, Foltran L, Guardascione M, Iacono D, Ongaro E, Fasola G, Puglisi F. Preoperative treatments in borderline resectable and locally advanced pancreatic cancer: current evidence and new perspectives. Crit Rev Oncol Hematol 2023; 186:104013. [PMID: 37116817 DOI: 10.1016/j.critrevonc.2023.104013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 04/10/2023] [Accepted: 04/24/2023] [Indexed: 04/30/2023] Open
Abstract
Surgery is the only curative treatment for non-metastatic pancreatic adenocarcinoma, but less than 20% of patients present a resectable disease at diagnosis. Treatment strategies and disease definition for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) vary in the different cancer centres. Preoperative chemotherapy (CT) is the standard of care for both BRPC and LAPC patients, however literature data are still controversial concerning the type, dose and duration of the different CT regimens, as well as regarding the integration of radiotherapy (RT) or chemoradiation (CRT) in the therapeutic algorithm. In this unsettled debate, we aimed at focusing on the therapeutic regimens currently in use and relative literature data, to report international trials comparing the available therapeutic options or explore the introduction of new pharmacological agents, and to analyse possible new scenarios in microenvironment evaluation before and after neoadjuvant therapies or in patients' selection at a molecular level.
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Affiliation(s)
- Marco de Scordilli
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Anna Michelotti
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Oncology, ASUFC University Hospital of Udine, 33100 Udine, Italy.
| | - Diego Zara
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Lorenza Palmero
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Martina Alberti
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Oncology, ASUFC University Hospital of Udine, 33100 Udine, Italy.
| | - Claudia Noto
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Fabiana Totaro
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Michela Guardascione
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Donatella Iacono
- Department of Oncology, ASUFC University Hospital of Udine, 33100 Udine, Italy.
| | - Elena Ongaro
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Gianpiero Fasola
- Department of Oncology, ASUFC University Hospital of Udine, 33100 Udine, Italy.
| | - Fabio Puglisi
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
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23
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Velasco RM, García AG, Sánchez PJ, Sellart IM, Sánchez-Arévalo Lobo VJ. Tumour microenvironment and heterotypic interactions in pancreatic cancer. J Physiol Biochem 2023; 79:179-192. [PMID: 35102531 DOI: 10.1007/s13105-022-00875-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/18/2022] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a disease with a survival rate of 9%; this is due to its chemoresistance and the large tumour stroma that occupies most of the tumour mass. It is composed of a large number of cells of the immune system, such as Treg cells, tumour-associated macrophages (TAMs), myeloid suppressor cells (MDCs) and tumour-associated neutrophiles (TANs) that generate an immunosuppressive environment by the release of inflammatory cytokines. Moreover, cancer-associated fibroblast (CAFs) provide a protective coverage that would difficult the access of chemotherapy to the tumour. According to this, new therapies that could remodel this heterogeneous tumour microenvironment, such as adoptive T cell therapies (ACT), immune checkpoint inhibitors (ICI), and CD40 agonists, should be developed for targeting PDA. This review organizes the different cell populations found in the tumour stroma involved in tumour progression in addition to the different therapies that are being studied to counteract the tumour.
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Affiliation(s)
- Raúl Muñoz Velasco
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Ana García García
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Paula Jiménez Sánchez
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Inmaculada Montanuy Sellart
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
| | - Víctor Javier Sánchez-Arévalo Lobo
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain.
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain.
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24
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Sinha M, Betts C, Zhang L, Griffith MJ, Solman I, Chen B, Liu E, Tamaki W, Stultz J, Marquez J, Sivagnanam S, Cheung A, Pener D, Fahlman A, Taber E, Lerner K, Crocker M, Todd K, Rajagopalan B, Ware C, Bridge M, Vo J, Dragomanovich H, Sudduth-Klinger J, Vaccaro G, Lopez CD, Tempero M, Coussens LM, Fong L. Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. J Immunother Cancer 2023; 11:jitc-2022-005425. [PMID: 36593070 PMCID: PMC9809229 DOI: 10.1136/jitc-2022-005425] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER NCT02562898.
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Affiliation(s)
- Meenal Sinha
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Courtney Betts
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Li Zhang
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA,Department of Biostatistics, University of California, San Francisco, California, USA
| | - Madeline J Griffith
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | | | - Brandon Chen
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Eric Liu
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Whitney Tamaki
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Jacob Stultz
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Jaqueline Marquez
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Shamilene Sivagnanam
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alexander Cheung
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Denise Pener
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Anne Fahlman
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Erin Taber
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Kimberly Lerner
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Matthew Crocker
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Kendra Todd
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Brindha Rajagopalan
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Clarisha Ware
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Mark Bridge
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Johnson Vo
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Hannah Dragomanovich
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Julie Sudduth-Klinger
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Gina Vaccaro
- Medical Oncology, Providence Portland Medical Center, Portland, Oregon, USA
| | - Charles D Lopez
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA,Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Margaret Tempero
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Lisa M Coussens
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Lawrence Fong
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA,Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
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25
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Tumor immunology. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00003-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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26
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Huang X, Zhang G, Tang TY, Gao X, Liang TB. Personalized pancreatic cancer therapy: from the perspective of mRNA vaccine. Mil Med Res 2022; 9:53. [PMID: 36224645 PMCID: PMC9556149 DOI: 10.1186/s40779-022-00416-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity, especially in genetic alteration and microenvironment. Conventional therapeutic strategies for pancreatic cancer usually suffer resistance, highlighting the necessity for personalized precise treatment. Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting, minimal nonspecific effects, broad therapeutic window, low toxicity, and induction of persistent immunological memory. Multiple conventional vaccines based on the cells, microorganisms, exosomes, proteins, peptides, or DNA against pancreatic cancer have been developed; however, their overall efficacy remains unsatisfactory. Compared with these vaccine modalities, messager RNA (mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment, and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer. This review summarizes the current progress on pancreatic cancer vaccines, highlights the superiority of mRNA vaccines over other conventional vaccines, and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.
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Affiliation(s)
- Xing Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Gang Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Tian-Yu Tang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Xiang Gao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Ting-Bo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
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Neoantigens and their clinical applications in human gastrointestinal cancers. World J Surg Oncol 2022; 20:321. [PMID: 36171610 PMCID: PMC9520945 DOI: 10.1186/s12957-022-02776-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 09/16/2022] [Indexed: 12/24/2022] Open
Abstract
Background Tumor-specific neoantigens are ideal targets for cancer immunotherapy. As research findings have proved, neoantigen-specific T cell activity is immunotherapy’s most important determinant. Main text There is sufficient evidence showing the role of neoantigens in clinically successful immunotherapy, providing a justification for targeting. Because of the significance of the pre-existing anti-tumor immune response for the immune checkpoint inhibitor, it is believed that personalized neoantigen-based therapy may be an imperative approach for cancer therapy. Thus, intensive attention is given to strategies targeting neoantigens for the significant impact with other immunotherapies, such as the immune checkpoint inhibitor. Today, several algorithms are designed and optimized based on Next-Generation Sequencing and public databases, including dbPepNeo, TANTIGEN 2.0, Cancer Antigenic Peptide Database, NEPdb, and CEDAR databases for predicting neoantigens in silico that stimulates the development of T cell therapies, cancer vaccine, and other ongoing immunotherapy approaches. Conclusions In this review, we deliberated the current developments in understanding and recognition of the immunogenicity of newly found gastrointestinal neoantigens as well as their functions in immunotherapies and cancer detection. We also described how neoantigens are being developed and how they might be used in the treatment of GI malignancies.
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Mukherji R, Debnath D, Hartley ML, Noel MS. The Role of Immunotherapy in Pancreatic Cancer. Curr Oncol 2022; 29:6864-6892. [PMID: 36290818 PMCID: PMC9600738 DOI: 10.3390/curroncol29100541] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 01/13/2023] Open
Abstract
Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.
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Affiliation(s)
- Reetu Mukherji
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Dipanjan Debnath
- Department of Internal Medicine, Medstar Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA
| | - Marion L. Hartley
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Marcus S. Noel
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
- Correspondence:
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29
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Zhang J, Li R, Huang S. The immunoregulation effect of tumor microenvironment in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:951019. [PMID: 35965504 PMCID: PMC9365986 DOI: 10.3389/fonc.2022.951019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer has the seventh highest death rate of all cancers. The absence of any serious symptoms, coupled with a lack of early prognostic and diagnostic markers, makes the disease untreatable in most cases. This leads to a delay in diagnosis and the disease progresses so there is no cure. Only about 20% of cases are diagnosed early. Surgical removal is the preferred treatment for cancer, but chemotherapy is standard for advanced cancer, although patients can eventually develop drug resistance and serious side effects. Chemoresistance is multifactorial because of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment (TME). Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. This review focuses on the immune-related components of TME and the interactions between tumor cells and TME during the development and progression of pancreatic cancer, including immunosuppression, tumor dormancy and escape. Finally, we discussed a variety of immune components-oriented immunotargeting drugs in TME from a clinical perspective.
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Affiliation(s)
| | - Renfeng Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuai Huang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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30
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Smith C, Zheng W, Dong J, Wang Y, Lai J, Liu X, Yin F. Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy. World J Gastroenterol 2022; 28:3297-3313. [PMID: 36158269 PMCID: PMC9346457 DOI: 10.3748/wjg.v28.i27.3297] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/22/2022] [Accepted: 06/19/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.
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Affiliation(s)
- Caitlyn Smith
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Wei Zheng
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Jixin Dong
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Yaohong Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Jinping Lai
- Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, United States
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
| | - Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212, United States
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31
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Wei J, Hui AM. The paradigm shift in treatment from Covid-19 to oncology with mRNA vaccines. Cancer Treat Rev 2022; 107:102405. [PMID: 35576777 PMCID: PMC9068246 DOI: 10.1016/j.ctrv.2022.102405] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 04/25/2022] [Accepted: 04/29/2022] [Indexed: 02/08/2023]
Abstract
mRNA vaccines have gained popularity over the last decade as a versatile tool for developing novel therapeutics. The recent success of coronavirus disease (COVID-19) mRNA vaccine has unlocked the potential of mRNA technology as a powerful therapeutic platform. In this review, we apprise the literature on the various types of cancer vaccines, the novel platforms available for delivery of the vaccines, the recent progress in the RNA-based therapies and the evolving role of mRNA vaccines for various cancer indications, along with a future strategy to treat the patients. Literature reveals that despite multifaceted challenges in the development of mRNA vaccines, the promising and durable efficacy of the RNA in pre-clinical and clinical studies deserves consideration. The introduction of mRNA-transfected DC vaccine is an approach that has gained interest for cancer vaccine development due to its ability to circumvent the necessity of DC isolation, ex vivo cultivation and re-infusion. The selection of appropriate antigen of interest remains one of the major challenges for cancer vaccine development. The rapid development and large-scale production of mRNA platform has enabled for the development of both personalized vaccines (mRNA 4157, mRNA 4650 and RO7198457) and tetravalent vaccines (BNT111 and mRNA-5671). In addition, mRNA vaccines combined with checkpoint modulators and other novel medications that reverse immunosuppression show promise, however further research is needed to discover which combinations are most successful and the best dosing schedule for each component. Each delivery route (intradermal, subcutaneous, intra tumoral, intranodal, intranasal, intravenous) has its own set of challenges to overcome, and these challenges will decide the best delivery method. In other words, while developing a vaccine design, the underlying motivation should be a reasonable combination of delivery route and format. Exploring various administration routes and delivery route systems has boosted the development of mRNA vaccines.
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Affiliation(s)
- Jiao Wei
- Shanghai Fosun Pharmaceutical Industrial Development, Co., Ltd., 1289 Yishan Road, Shanghai 200233, China; Fosun Pharma USA Inc, 91 Hartwell Avenue, Suite 305, Lexington, MA 02421, USA
| | - Ai-Min Hui
- Shanghai Fosun Pharmaceutical Industrial Development, Co., Ltd., 1289 Yishan Road, Shanghai 200233, China; Fosun Pharma USA Inc, 91 Hartwell Avenue, Suite 305, Lexington, MA 02421, USA.
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32
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Baleeiro RB, Bouwens CJ, Liu P, Di Gioia C, Dunmall LSC, Nagano A, Gangeswaran R, Chelala C, Kocher HM, Lemoine NR, Wang Y. MHC class II molecules on pancreatic cancer cells indicate a potential for neo-antigen-based immunotherapy. Oncoimmunology 2022; 11:2080329. [PMID: 35655709 PMCID: PMC9154752 DOI: 10.1080/2162402x.2022.2080329] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 11/05/2022] Open
Abstract
MHC class II expression is a hallmark of professional antigen-presenting cells and key to the induction of CD4+ T helper cells. We found that these molecules are ectopically expressed on tumor cells in a large proportion of patients with pancreatic ductal adenocarcinoma (PDAC) and on several PDAC cell lines. In contrast to the previous reports that tumoral expression of MHC-II in melanoma enabled tumor cells to evade immunosurveillance, the expression of MHC-II on PDAC cells neither protected cancer cells from Fas-mediated cell death nor caused T-cell suppression by engagement with its ligand LAG-3 on activated T-cells. In fact and surprisingly, the MHC-II/LAG-3 pathway contributed to CD4+ and CD8+ T-cell cytotoxicity toward MHC-II-positive PDAC cells. By combining bioinformatic tools and cell-based assays, we identified a number of immunogenic neo-antigens that can be presented by the patients' HLA class II alleles. Furthermore, CD4+ T-cells stimulated with neo-antigens were capable of recognizing and killing a human PDAC cell line expressing the mutated genes. To expand this approach to a larger number of PDAC patients, we show that co-treatment with IFN-γ and/or MEK/HDAC inhibitors induced tumoral MHC-II expression on MHC-II-negative tumors that are IFN-γ-resistant. Taken together, our data point to the possibility of harnessing MHC-II expression on PDAC cells for neo-antigen-based immunotherapy.
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Affiliation(s)
- Renato B. Baleeiro
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Christian J. Bouwens
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Peng Liu
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Carmela Di Gioia
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Louisa S. Chard Dunmall
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Ai Nagano
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Rathistevy Gangeswaran
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Claude Chelala
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Hemant M. Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Nicholas R. Lemoine
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
- Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySino-British, Zhengzhou, Henan, China
| | - Yaohe Wang
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
- Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySino-British, Zhengzhou, Henan, China
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Mesothelin: An Immunotherapeutic Target beyond Solid Tumors. Cancers (Basel) 2022; 14:cancers14061550. [PMID: 35326701 PMCID: PMC8946840 DOI: 10.3390/cancers14061550] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/12/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary This review summarizes the current knowledge on mesothelin’s function, its role in cancer, and opportunities for immunotherapeutic targeting of mesothelin. Immunotherapies including monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK-cells, targeted alpha therapies, and bispecific T cell engaging molecules are reviewed. We show future directions for mesothelin targeting in hematological malignancies, including acute myeloid leukemia. Abstract Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, and most recently in hematological malignancies, including acute myeloid leukemia (AML). Although the function of mesothelin is widely unknown, interactions with MUC16/CA125 indicate that mesothelin plays a role in the regulation of proliferation, growth, and adhesion signaling. Most research on mesothelin currently focuses on utilizing mesothelin to design targeted cancer therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK cells, bispecific T cell engaging molecules, and targeted alpha therapies, amongst others. Both in vitro and in vivo studies using different immunotherapeutic modalities in mesothelin-positive AML models highlight the potential impact of this approach as a unique opportunity to treat hard-to-cure AML.
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Hu H, Chen Y, Tan S, Wu S, Huang Y, Fu S, Luo F, He J. The Research Progress of Antiangiogenic Therapy, Immune Therapy and Tumor Microenvironment. Front Immunol 2022; 13:802846. [PMID: 35281003 PMCID: PMC8905241 DOI: 10.3389/fimmu.2022.802846] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/01/2022] [Indexed: 02/05/2023] Open
Abstract
Anti-angiogenesis therapy, a promising strategy against cancer progression, is limited by drug-resistance, which could be attributed to changes within the tumor microenvironment. Studies have increasingly shown that combining anti-angiogenesis drugs with immunotherapy synergistically inhibits tumor growth and progression. Combination of anti-angiogenesis therapy and immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed. The aim of this review is to discuss whether the combination of anti-angiogenesis therapy and immunotherapy can exert synergistic antitumor effects, which can provide a basis to exploring new targets and developing more advanced strategies.
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Affiliation(s)
- Haoyue Hu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.,Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and Technology, Chengdu, China
| | - Yue Chen
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Songtao Tan
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Silin Wu
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yan Huang
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Shengya Fu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.,Second Department of Oncology, Sichuan Friendship Hospital, Chengdu, China
| | - Feng Luo
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Jun He
- Department of Oncology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
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Kole C, Charalampakis N, Tsakatikas S, Frountzas M, Apostolou K, Schizas D. Immunotherapy in Combination with Well-Established Treatment Strategies in Pancreatic Cancer: Current Insights. Cancer Manag Res 2022; 14:1043-1061. [PMID: 35300059 PMCID: PMC8921671 DOI: 10.2147/cmar.s267260] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 02/11/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and fourth most common cause of death in developed countries. Despite improved survival rates after resection combined with adjuvant chemotherapy or neoadjuvant chemotherapy, recurrence still occurs in a high percentage of patients within the first 2 years after resection. Immunotherapy aims to improve antitumor immune responses and reduce toxicity providing a more specific, targeted therapy compared to chemotherapy and has been proved an efficient therapeutic tool for many solid tumors. In this work, we present the latest advances in PDAC treatment using a combination of immunotherapy with other interventions such as chemotherapy and/or radiation both at neoadjuvant and adjuvant setting. Moreover, we outline the role of the tumor microenvironment as a key barrier to immunotherapy efficacy and examine how immunotherapy biomarkers may be used to detect immunotherapy’s response.
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Affiliation(s)
- Christo Kole
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | | | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital, Athens, 185 37, Greece
| | - Maximos Frountzas
- First Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Hippocration General Hospital, Athens, 115 27, Greece
| | - Konstantinos Apostolou
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
- Correspondence: Dimitrios Schizas, First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece, Tel +306944505917, Fax +302132061766, Email
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36
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Shao J, Liu Q, Shen J, Qian X, Yan J, Zhu Y, Qiu X, Lu C, Cen L, Tian M, Du J, Liu B. Advanced Pancreatic Cancer Patient Benefit From Personalized Neoantigen Nanovaccine Based Immunotherapy: A Case Report. Front Immunol 2022; 13:799026. [PMID: 35273594 PMCID: PMC8901600 DOI: 10.3389/fimmu.2022.799026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 02/02/2022] [Indexed: 11/13/2022] Open
Abstract
Personal neoantigen vaccines are considered to be effective methods for inducing, amplifying and diversifying antitumor T cell responses. We recently conducted a clinical study that combined neoantigen nanovaccine with anti-PD-1 antibody. Here, we reported a case with a clear beneficial outcome from this treatment. We established a process that includes comprehensive identification of individual mutations, computational prediction of new epitopes, and design and manufacture of unique nanovaccines for this patient. Nanovaccine started after a relapse in third-line treatment. We assessed the patient's clinical outcome and circulating immune response. In this advanced pancreatic cancer patient, the OS associated with the vaccine treatment was 10.5 months. A peptide-specific T-cell response against 9 of the 12 vaccine peptides could be detected sequentially. Robust neoantigen-specific T cell responses were also detected by IFN-γ ELISPOT and intracellular cytokine staining. In conclusion, sustained functional neoantigen-specific T cell therapy combined with immune checkpoint targeting may be well suited to help control progressive metastatic pancreatic cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Juan Du
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
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37
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Diverse and precision therapies open new horizons for patients with advanced pancreatic ductal adenocarcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:10-24. [PMID: 34538570 DOI: 10.1016/j.hbpd.2021.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 08/31/2021] [Indexed: 02/05/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer-related death, and most patients are with advanced disease when diagnosed. At present, despite a variety of treatments have been developed for PDAC, few effective treatment options are available; on the other hand, PDAC shows significant resistance to chemoradiotherapy, targeted therapy, and immunotherapy due to its heterogeneous genetic profile, molecular signaling pathways, and complex tumor immune microenvironment. Nevertheless, over the past decades, there have been many new advances in the key theory and understanding of the intrinsic mechanisms and complexity of molecular biology and molecular immunology in pancreatic cancer, based on which more and more diverse new means and reasonable combination strategies for PDAC treatment have been developed and preliminary breakthroughs have been made. With the continuous exploration, from surgical local treatment to comprehensive medical management, the research-diagnosis-management system of pancreatic cancer is improving. This review focused on the variety of treatments for advanced PDAC, including traditional chemotherapy, targeted therapy, immunotherapy, microenvironment matrix regulation as well as the treatment targeting epigenetics, metabolism and cancer stem cells. We pointed out the current research bottlenecks and future exploration directions.
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38
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Pretta A, Lai E, Persano M, Donisi C, Pinna G, Cimbro E, Parrino A, Spanu D, Mariani S, Liscia N, Dubois M, Migliari M, Impera V, Saba G, Pusceddu V, Puzzoni M, Ziranu P, Scartozzi M. Uncovering key targets of success for immunotherapy in pancreatic cancer. Expert Opin Ther Targets 2021; 25:987-1005. [PMID: 34806517 DOI: 10.1080/14728222.2021.2010044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. AREAS COVERED In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. EXPERT OPINION The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Erika Cimbro
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Alissa Parrino
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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Delitto D, Zabransky DJ, Chen F, Thompson ED, Zimmerman JW, Armstrong TD, Leatherman JM, Suri R, Lopez-Vidal TY, Huff AL, Lyman MR, Guinn SR, Baretti M, Kagohara LT, Ho WJ, Azad NS, Burns WR, He J, Wolfgang CL, Burkhart RA, Zheng L, Yarchoan M, Zaidi N, Jaffee EM. Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection. Oncoimmunology 2021; 10:2001159. [PMID: 34777919 PMCID: PMC8583296 DOI: 10.1080/2162402x.2021.2001159] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.
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Affiliation(s)
- Daniel Delitto
- Department of Surgery, Stanford University School of Medicine, Stanford, USA.,Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Daniel J Zabransky
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Fangluo Chen
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Elizabeth D Thompson
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jacquelyn W Zimmerman
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Todd D Armstrong
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - James M Leatherman
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Reecha Suri
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Tamara Y Lopez-Vidal
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Amanda L Huff
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Melissa R Lyman
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Samantha R Guinn
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Marina Baretti
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Luciane T Kagohara
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Won Jin Ho
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Nilofer S Azad
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - William R Burns
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | | | - Richard A Burkhart
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Lei Zheng
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA.,The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Mark Yarchoan
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Neeha Zaidi
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Elizabeth M Jaffee
- The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, USA.,The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, USA.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA
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Anderson EM, Thomassian S, Gong J, Hendifar A, Osipov A. Advances in Pancreatic Ductal Adenocarcinoma Treatment. Cancers (Basel) 2021; 13:5510. [PMID: 34771675 PMCID: PMC8583016 DOI: 10.3390/cancers13215510] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies among all cancers. Despite curative intent, surgery and the use of standard cytotoxic chemotherapy and radiation therapy, PDAC remains treatment-resistant. In recent years, more contemporary treatment modalities such as immunotherapy via checkpoint inhibition have shown some promise in many other malignancies, yet PDAC still eludes an effective curative treatment. In investigating these phenomena, research has suggested that the significant desmoplastic and adaptive tumor microenvironment (TME) of PDAC promote the proliferation of immunosuppressive cells and act as major obstacles to treatment efficacy. In this review, we explore challenges associated with the treatment of PDAC, including its unique immunosuppressive TME. This review examines the role of surgery in PDAC, recent advances in surgical approaches and surgical optimization. We further focus on advances in immunotherapeutic approaches, including checkpoint inhibition, CD40 agonists, and discuss promising immune-based future strategies, such as therapeutic neoantigen cancer vaccines as means of overcoming the resistance mechanisms which underly the dense stroma and immune milieu of PDAC. We also explore unique signaling, TME and stromal targeting via novel small molecule inhibitors, which target KRAS, FAK, CCR2/CCR5, CXCR4, PARP and cancer-associated fibroblasts. This review also explores the most promising strategy for advancement in treatment of pancreatic cancer by reviewing contemporary combinatorial approaches in efforts to overcome the treatment refractory nature of PDAC.
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Affiliation(s)
- Eric M. Anderson
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Shant Thomassian
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (S.T.); (J.G.); (A.H.)
| | - Jun Gong
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (S.T.); (J.G.); (A.H.)
| | - Andrew Hendifar
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (S.T.); (J.G.); (A.H.)
| | - Arsen Osipov
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (S.T.); (J.G.); (A.H.)
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Abdul Rahman R, Lamarca A, Hubner RA, Valle JW, McNamara MG. The Microbiome as a Potential Target for Therapeutic Manipulation in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13153779. [PMID: 34359684 PMCID: PMC8345056 DOI: 10.3390/cancers13153779] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic cancer is one of the most lethal cancers. It is a difficult cancer to treat, and the complexity surrounding the pancreatic tumour is one of the contributing factors. The microbiome is the collection of microorganisms within an environment and its genetic material. They reside on body surfaces and most abundantly within the human gut in symbiotic balance with their human host. Disturbance in the balance can lead to many diseases, including cancers. Significant advances have been made in cancer treatment since the introduction of immunotherapy, and the microbiome may play a part in the outcome and survival of patients with cancer, especially those treated with immunotherapy. Immunotherapy use in pancreatic cancer remains challenging. This review will focus on the potential interaction of the microbiome with pancreas cancer and how this could be manipulated. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and radiotherapy techniques, the outcome for patients with PDAC remains poor. Poor prognosis is multifactorial, including the likelihood of sub-clinical metastatic disease at presentation, late-stage at presentation, absence of early and reliable diagnostic biomarkers, and complex biology surrounding the extensive desmoplastic PDAC tumour micro-environment. Microbiota refers to all the microorganisms found in an environment, whereas microbiome is the collection of microbiota and their genome within an environment. These organisms reside on body surfaces and within mucosal layers, but are most abundantly found within the gut. The commensal microbiome resides in symbiosis in healthy individuals and contributes to nutritive, metabolic and immune-modulation to maintain normal health. Dysbiosis is the perturbation of the microbiome that can lead to a diseased state, including inflammatory bowel conditions and aetiology of cancer, such as colorectal and PDAC. Microbes have been linked to approximately 10% to 20% of human cancers, and they can induce carcinogenesis by affecting a number of the cancer hallmarks, such as promoting inflammation, avoiding immune destruction, and microbial metabolites can deregulate host genome stability preceding cancer development. Significant advances have been made in cancer treatment since the advent of immunotherapy. The microbiome signature has been linked to response to immunotherapy and survival in many solid tumours. However, progress with immunotherapy in PDAC has been challenging. Therefore, this review will focus on the available published evidence of the microbiome association with PDAC and explore its potential as a target for therapeutic manipulation.
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Affiliation(s)
- Rozana Abdul Rahman
- Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester M20 4BX, UK;
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK; (A.L.); (R.A.H.)
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK; (A.L.); (R.A.H.)
| | - Juan W. Valle
- Division of Cancer Sciences, University of Manchester/Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK;
| | - Mairéad G. McNamara
- Division of Cancer Sciences, University of Manchester/Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK;
- Correspondence:
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Di Federico A, Tateo V, Parisi C, Formica F, Carloni R, Frega G, Rizzo A, Ricci D, Di Marco M, Palloni A, Brandi G. Hacking Pancreatic Cancer: Present and Future of Personalized Medicine. Pharmaceuticals (Basel) 2021; 14:677. [PMID: 34358103 PMCID: PMC8308563 DOI: 10.3390/ph14070677] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.
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Affiliation(s)
- Alessandro Di Federico
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Valentina Tateo
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Claudia Parisi
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Francesca Formica
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Riccardo Carloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Giorgio Frega
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Alessandro Rizzo
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Dalia Ricci
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Mariacristina Di Marco
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Andrea Palloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
| | - Giovanni Brandi
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.D.F.); (V.T.); (C.P.); (F.F.); (R.C.); (G.F.); (A.R.); (D.R.); (M.D.M.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy
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Cancer Vaccines: Promising Therapeutics or an Unattainable Dream. Vaccines (Basel) 2021; 9:vaccines9060668. [PMID: 34207062 PMCID: PMC8233841 DOI: 10.3390/vaccines9060668] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/11/2021] [Accepted: 06/13/2021] [Indexed: 02/08/2023] Open
Abstract
The advent of cancer immunotherapy has revolutionized the field of cancer treatment and offers cancer patients new hope. Although this therapy has proved highly successful for some patients, its efficacy is not all encompassing and several cancer types do not respond. Cancer vaccines offer an alternate approach to promote anti-tumor immunity that differ in their mode of action from antibody-based therapies. Cancer vaccines serve to balance the equilibrium of the crosstalk between the tumor cells and the host immune system. Recent advances in understanding the nature of tumor-mediated tolerogenicity and antigen presentation has aided in the identification of tumor antigens that have the potential to enhance anti-tumor immunity. Cancer vaccines can either be prophylactic (preventative) or therapeutic (curative). An exciting option for therapeutic vaccines is the emergence of personalized vaccines, which are tailor-made and specific for tumor type and individual patient. This review summarizes the current standing of the most promising vaccine strategies with respect to their development and clinical efficacy. We also discuss prospects for future development of stem cell-based prophylactic vaccines.
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Alzhrani R, Alsaab HO, Vanamal K, Bhise K, Tatiparti K, Barari A, Sau S, Iyer AK. Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes. ADVANCED THERAPEUTICS 2021; 4:2000262. [PMID: 34212073 PMCID: PMC8240487 DOI: 10.1002/adtp.202000262] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.
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Affiliation(s)
- Rami Alzhrani
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Kushal Vanamal
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ketki Bhise
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Katyayani Tatiparti
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ayatakshi Barari
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Samaresh Sau
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Arun K. Iyer
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States
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Hue JJ, Bingmer K, Sugumar K, Markt SC, Rothermel LD, Hardacre JM, Ammori JB, Winter JM, Ocuin LM. Immunotherapy Is Associated with a Survival Benefit in Patients Receiving Chemotherapy for Metastatic Pancreatic Cancer. J Pancreat Cancer 2021; 7:31-38. [PMID: 33937617 PMCID: PMC8080907 DOI: 10.1089/pancan.2021.0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2021] [Indexed: 12/27/2022] Open
Abstract
Background: Immunotherapy (IT) has led to improved survival in several common cancers but success in pancreatic ductal adenocarcinoma (PDAC) has been limited. We analyzed if combination IT-chemotherapy (IT-CT) is associated with improved survival compared with chemotherapy alone (CT) in patients with metastatic PDAC. Methods: The National Cancer Database (2004-2016) was queried for patients who were diagnosed with metastatic PDAC. Patients were categorized by treatment group: CT only and IT-CT. Patients were excluded if they received radiation or a surgical procedure. The primary outcome was overall survival. Results: A total of 59,289 patients were identified, of whom 58,947 (99.4%) received CT and 342 (0.6%) received IT-CT. The IT-CT group was younger, had fewer comorbidities, and was more often treated at an academic center. The utilization of multiagent CT was similar between the groups. Median survival of patients treated with IT-CT was longer than CT alone (7.9 months vs. 6.3 months, p = 0.005). On multivariable analysis, receipt of IT-CT was associated with a survival advantage as compared with CT (hazard ratio = 0.86, 95% confidence intervals 0.76-0.97) when adjusting for demographics and type of CT regimen. Conclusion: In patients with metastatic PDAC, it appears that combination IT-CT may perhaps be associated with a survival advantage compared with CT alone.
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Affiliation(s)
- Jonathan J Hue
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Katherine Bingmer
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Kavin Sugumar
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Sarah C Markt
- Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Luke D Rothermel
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Jeffrey M Hardacre
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - John B Ammori
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Jordan M Winter
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Lee M Ocuin
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
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Elsayed M, Abdelrahim M. The Latest Advancement in Pancreatic Ductal Adenocarcinoma Therapy: A Review Article for the Latest Guidelines and Novel Therapies. Biomedicines 2021; 9:389. [PMID: 33917380 PMCID: PMC8067364 DOI: 10.3390/biomedicines9040389] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the US, and it is expected to be the second leading cause of cancer deaths by 2030. The lack of effective early screening tests and alarming symptoms with early undetectable micro-metastasis at the time of presentation play a vital role in the high death rate from pancreatic cancer. In addition to this, the low mutation burden in pancreatic cancer, low immunological profile, dense tumorigenesis stroma, and decreased tumor sensitivity to cytotoxic drugs contribute to the low survival rates in PDAC patients. Despite breakthroughs in chemotherapeutic and immunotherapeutic drugs, pancreatic cancer remains one of the solid tumors that exhibit meager curative rates. Therefore, researchers must dedicate more effort to understanding the pathology and immunological behavior of PDAC, in addition to properly utilizing more advanced screening modalities and new therapeutic agents. In our review, we focus mainly on the latest updates from clinical guidelines and novel therapies that have been recently investigated or are under investigation for PDAC. We used PubMed as a search tool for finding original research articles addressing the latest developments in diagnosing and treating PDAC. Additionally, we also used the clinical trials published on clinicaltrialsgov as sources for our data.
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Affiliation(s)
- Marwa Elsayed
- School of Medicine, University of Missouri Kansas City, 2301 Holmes, St. Kansas City, MO 64018, USA;
| | - Maen Abdelrahim
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Weill Cornell Medical College, Institute of Academic Medicine, Houston, TX 77030, USA
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Brouwer TP, Vahrmeijer AL, de Miranda NFCC. Immunotherapy for pancreatic cancer: chasing the light at the end of the tunnel. Cell Oncol (Dordr) 2021; 44:261-278. [PMID: 33710604 PMCID: PMC7985121 DOI: 10.1007/s13402-021-00587-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Checkpoint blockade immunotherapy has had a significant impact on the survival of a subset of patients with advanced cancers. It has been particularly effective in immunogenic cancer types that present large numbers of somatic mutations in their genomes. To date, all conventional immunotherapies have failed to produce significant clinical benefits for patients diagnosed with pancreatic cancer, probably due to its poor immunogenic properties, including low numbers of neoantigens and highly immune-suppressive microenvironments. CONCLUSIONS Herein, we discuss advances that have recently been made in cancer immunotherapy and the potential of this field to deliver effective treatment options for pancreatic cancer patients. Preclinical investigations, combining different types of therapies, highlight possibilities to enhance anti-tumor immunity and to generate meaningful clinical responses in pancreatic cancer patients. Results from completed and ongoing (pre)clinical trials are discussed.
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Affiliation(s)
- Thomas P Brouwer
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands, PO Box 9600, 2300 RC
| | | | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands, PO Box 9600, 2300 RC.
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48
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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49
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Role of targeted immunotherapy for pancreatic ductal adenocarcinoma (PDAC) treatment: An overview. Int Immunopharmacol 2021; 95:107508. [PMID: 33725635 DOI: 10.1016/j.intimp.2021.107508] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/18/2021] [Accepted: 02/12/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors with a high mortality rate and poor survival rate. Depending on the tumor stage, PDAC is either treated by resection surgery, chemotherapies, or radiotherapies. Various chemotherapeutic agents have been used to treat PDAC, alone or in combination. Despite the combinations, chemotherapy exhibits many side-effects leading to an increase in the toxicity profile amongst the PDAC patients. Additionally, these standard chemotherapeutic agents have only a modest impact on patient survival due to their limited efficacy. PDAC was previously considered as an immunologically silent malignancy, but recent findings have demonstrated that effective immune-mediated tumor cell death can be used for its treatment. PDAC is characterized by an immunosuppressive tumor microenvironment accompanied by the major expression of myeloid-derived suppressor cells (MDSC) and M2 tumor-associated macrophages. In contrast, the expression of CD8+ T cells is significantly low. Additionally, infiltration of mast cells in PDAC correlates with the poor prognosis. Immunotherapeutic agents target the immunity mediators and empower them to suppress the tumor and effectively treat PDAC. Different targets are studied and exploited to induce an antitumor immune response in PDAC patients. In recent times, site-specific delivery of immunotherapeutics also gained attention among researchers to effectively treat PDAC. In the present review, existing immunotherapies for PDAC treatment along with their limitations are addressed in detail. The review also includes the pathophysiology, traditional strategies and significance of targeted immunotherapies to combat PDAC effectively. Separately, the identification of ideal targets for the targeted therapy of PDAC is also reviewed exhaustively. Additionally, the review also addresses the applications of targeted immunotherapeutics like checkpoint inhibitors, adoptive T-cell therapy etc.
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50
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Wattenberg MM, Herrera VM, Giannone MA, Gladney WL, Carpenter EL, Beatty GL. Systemic inflammation is a determinant of outcomes of CD40 agonist-based therapy in pancreatic cancer patients. JCI Insight 2021; 6:145389. [PMID: 33497362 PMCID: PMC8021099 DOI: 10.1172/jci.insight.145389] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies.
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Affiliation(s)
- Max M Wattenberg
- Division of Hematology-Oncology, Department of Medicine, and.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Veronica M Herrera
- Division of Hematology-Oncology, Department of Medicine, and.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael A Giannone
- Division of Hematology-Oncology, Department of Medicine, and.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Whitney L Gladney
- Division of Hematology-Oncology, Department of Medicine, and.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Erica L Carpenter
- Division of Hematology-Oncology, Department of Medicine, and.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Gregory L Beatty
- Division of Hematology-Oncology, Department of Medicine, and.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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