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Gutiu AG, Zhao L, Marrah AJ, Maher AJ, Voss BB, Mayberry TG, Cowan BC, Wakefield MR, Fang Y. Promising immunotherapeutic treatments for colon cancer. Med Oncol 2025; 42:175. [PMID: 40266497 DOI: 10.1007/s12032-025-02724-2] [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: 01/11/2025] [Accepted: 04/14/2025] [Indexed: 04/24/2025]
Abstract
Colon cancer continues to predominate as one of the most common causes of morbidity and mortality worldwide due to its subtle symptomology and multifactorial etiology. Currently, the standard treatment approach involves surgical resection for localized tumors and adjuvant chemotherapy (AC) for cancers that have spread or invaded locally. Unfortunately, this treatment strategy may not be effective for advanced, metastatic stages of the disease or in instances of recurrence. However, advancements in immunotherapy have demonstrated promising results in the field of medical oncology, which could redefine the way patients and clinicians view the disease. These treatments have shown benefit and have the potential to be superior to the current interventions available for afflicted patients. The application of immunotherapy in conjunction with traditional treatments may improve the outcomes of patients suffering from colon cancer and decrease the burden this disease has on patients. Furthermore, more effective treatments in the form of conjunction immunological, surgical, and chemotherapeutic techniques may shorten treatment courses and lead to better long-term effects. This review paper investigates immunotherapeutic interventions for colon cancer, which include immune checkpoint inhibitors, oncolytic virotherapy, cancer vaccines, cytokine therapy, and CAR-T. Such a study might provide more information for clinicians to treat patients with colon cancer in the advanced stages or in recurrence.
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Affiliation(s)
- Arturo G Gutiu
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA, 50266, USA
| | - Lei Zhao
- Department of Respiratory Medicine, The 2nd People's Hospital of Hefei and Hefei Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Austin J Marrah
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Austin J Maher
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Brady B Voss
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Trenton G Mayberry
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Braydon C Cowan
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA, 50266, USA.
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, West Des Moines, IA, 50266, USA.
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2
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Palma M. Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges. Vaccines (Basel) 2025; 13:344. [PMID: 40333213 PMCID: PMC12030785 DOI: 10.3390/vaccines13040344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 05/09/2025] Open
Abstract
Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body's immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody-drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines-including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines-aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes.
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Affiliation(s)
- Marco Palma
- Institute for Globally Distributed Open Research and Education (IGDORE), 03181 Torrevieja, Spain
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Paul S, Zhou S. Six events that shaped antibody approvals in oncology. Front Immunol 2025; 16:1533796. [PMID: 39995677 PMCID: PMC11847691 DOI: 10.3389/fimmu.2025.1533796] [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: 11/24/2024] [Accepted: 01/20/2025] [Indexed: 02/26/2025] Open
Abstract
A little over twenty-five years ago, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) approved the chimeric antibody rituximab which fundamentally altered the landscape of anti-cancer drugs. While only a few antibodies were approved in the immediate years that followed the rituximab approval, the last decade saw a wave of antibody-drug approvals in the oncology arena. In the last three years, the EMA and FDA greenlighted eighteen antibodies, the majority of them designed in the formats of antibody-drug conjugates (ADC) and bispecific antibodies (BsAb). While the use of ADC and BsAb formats and the current rapid pace of approvals appear routine and almost inevitable, such progress was thought to be quite improbable in the early days of therapeutic antibody development. To understand how we arrived at the current state of antibody development in oncology, we focus on six monumental events that shaped antibody approvals over the last two and half decades. We examine the circumstances that led to the approval of rituximab and trastuzumab, the first successful antibodies for the treatment of hematologic and solid cancers. We detail the generation of the ADC and BsAb formats that dramatically augmented antibody-mediated precision cytotoxicity. Finally, we explore the development of ipilimumab, the first immune checkpoint-inhibiting antibody that activates the immune system to kill cancer cells, and the discovery that allowed the use of checkpoint inhibitors across all cancer types based on the presence of genetic markers. Revisiting these key events provides critical insights into the process of antibody development in oncology.
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Affiliation(s)
- Suman Paul
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Shibin Zhou
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
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4
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Bouligny IM, Montalban-Bravo G, Sasaki K, Daver N, Jabbour E, Alvarado Y, DiNardo CD, Ravandi F, Borthakur G, Pemmaraju N, Kadia T, Masarova L, Takahashi K, Andreeff M, Bazinet A, Yang H, Kanagal R, Pierce S, Meyer M, Huang X, Garcia-Manero G. A phase II trial of ipilimumab, nivolumab, or ipilimumab and nivolumab with or without azacitidine in relapsed or refractory myelodysplastic neoplasms. Leukemia 2025; 39:524-528. [PMID: 39551874 DOI: 10.1038/s41375-024-02457-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 10/24/2024] [Accepted: 10/29/2024] [Indexed: 11/19/2024]
Affiliation(s)
- Ian M Bouligny
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Guillermo Montalban-Bravo
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Koji Sasaki
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Naval Daver
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Elias Jabbour
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Yesid Alvarado
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Courtney D DiNardo
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Farhad Ravandi
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Gautam Borthakur
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Naveen Pemmaraju
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Tapan Kadia
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Lucia Masarova
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Koichi Takahashi
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Michael Andreeff
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Alexandre Bazinet
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Hui Yang
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Rashmi Kanagal
- The University of Texas MD Anderson Cancer Center, Department of Hematopathology, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Sherry Pierce
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Meghan Meyer
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Xuelin Huang
- The University of Texas MD Anderson Cancer Center, Department of Biostatistics, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Guillermo Garcia-Manero
- The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
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Gencsoy Eker S, Inetas Yengin G, Tatar C, Oktem G. A Comprehensive Review of the Mechanisms and Clinical Development of Monoclonal Antibodies in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1479:181-203. [PMID: 39666264 DOI: 10.1007/5584_2024_838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Cancer is still the disease that ranks first in human mortality in the twenty-first century. In the last 20 years, the concept of molecular targeted therapy has come to the fore with the use of small molecule agents or signal transduction inhibitors that show anticancer effects for certain types of cancer. Monoclonal antibodies, which have a therapeutic effect, especially by providing signal transduction inhibition, are used clinically as first-line treatment in various types of cancer. Molecular targeted therapies are critical for eliminating the adverse effects and drug resistance problems that occur in traditional cancer treatments. This review summarizes current information on various targeted therapeutic agents, including the structure and classification of monoclonal antibodies, their production methods and mechanisms of action, the monoclonal antibodies used in clinical trials, the complement system mechanism and cancer relationship, and the relationship between complement-dependent cytotoxicity and monoclonal antibodies.
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Affiliation(s)
- Selen Gencsoy Eker
- Department of Stem Cell, Graduate School of Health Sciences, Ege University, Izmir, Turkey
| | - Gizem Inetas Yengin
- Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey
| | - Cansu Tatar
- Department of Molecular Biology and Genetics, Yildiz Technical University, Istanbul, Turkey
| | - Gulperi Oktem
- Department of Stem Cell, Graduate School of Health Sciences, Ege University, Izmir, Turkey.
- Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
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Tamuli B, Ghagare R, Mandal G. Design, Production, and Optimization of Antigen-Specific Recombinant Antitumor Dimeric IgA Antibody. Methods Mol Biol 2025; 2909:119-129. [PMID: 40029519 DOI: 10.1007/978-1-0716-4442-3_9] [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] [Indexed: 03/05/2025]
Abstract
Available cancer immunotherapies are currently restricted to extracellular targets, while chemotherapy is the only option for intracellular targets, such as mutant KRAS. Antibodies are serum immunoglobulins, each having high binding specificity against particular antigens. Patients produce antibody responses against abnormally expressed self-proteins and neoantigens presented by the cancer cells. However, despite their infiltration into the tumor beds, many times the magnitude of the antitumor antibodies produced by spontaneously infiltrated B lymphocytes remains insufficient to control tumor growth. Recent work has established that dimeric IgA antibodies can target intracellular targets inside cancer cells expressing the polymeric immunoglobulin receptor (pIgR). Here, we thoroughly discuss the entire process of recombinant production of intracellular antigen-specific dimeric IgA antibodies that could be utilized for targeting oncodrivers inside tumor cells.
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Affiliation(s)
- Baishali Tamuli
- Cancer Immune Environment and Therapeutics Lab, Tumor Immunology and Immunotherapy, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Rutik Ghagare
- Division of Cancer Biology, BRIC-Institute of Life Sciences, Bhubaneswar, India
| | - Gunjan Mandal
- Division of Cancer Biology, BRIC-Institute of Life Sciences, Bhubaneswar, India.
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Abusaif MS, Ragab A, Fayed EA, Ammar YA, Gowifel AMH, Hassanin SO, Ahmed GE, Gohar NA. Exploring a novel thiazole derivatives hybrid with fluorinated-indenoquinoxaline as dual inhibitors targeting VEGFR2/AKT and apoptosis inducers against hepatocellular carcinoma with docking simulation. Bioorg Chem 2025; 154:108023. [PMID: 39644617 DOI: 10.1016/j.bioorg.2024.108023] [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: 10/13/2024] [Revised: 11/17/2024] [Accepted: 11/30/2024] [Indexed: 12/09/2024]
Abstract
Hepatocellular carcinoma (HCC) ranks as the third most prevalent reason for cancer-related death on a global scale. Tyrosine kinase inhibitors (TKIs) continue to be the primary treatment option for advanced hepatocellular carcinoma. A series of fluoro-11H-indeno[1,2-b]quinoxaline derivatives as an HCC drug targeting the VEGFR2/AKT axis was designed and synthesized. The novel compounds were investigated against HepG-2 and HuH-7 liver tumor cell lines. Compound 5 was the most active derivative against HepG-2 and HuH-7 cell lines with IC50 = 0.75 ± 0.04 and 3.43 ± 0.16 μM, respectively, in contrast to Sorafenib which shows IC50 values of 5.23 ± 0.31 and 4.58 ± 0.21 μM, respectively. IC50 values on normal liver cells (THLE-2) show that all tests are more selective than Sorafenib, prompting further research. The most promising cytotoxic compound has virtually equal VEGFR2 inhibition efficacy to Sorafenib. The total VEGFR2 and p-VEGFR2 inhibitory effects were subsequently evaluated, showing 38.32 % and 77.64 % attenuation, respectively. Compound 5 also reduced total and phosphorylated AKT concentrations in HepG-2 cells by 55.29 % and 78.01 %, respectively. Furthermore, Compound 5 upregulated BAX and caspase-3 and downregulated Bcl-2 to promote apoptosis. Hybrid 5 stops HepG-2's cell cycle at the S phase 48.02 % higher than untreated. Docking experiments assessed AKT and VEGFR2 binding patterns.
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Affiliation(s)
- Moustafa S Abusaif
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt.
| | - Ahmed Ragab
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt; Chemistry Department, Faculty of Science, Galala University, Galala City, 43511, Suez, Egypt.
| | - Eman A Fayed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City 11754, Cairo, Egypt.
| | - Yousry A Ammar
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt
| | - Ayah M H Gowifel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt
| | - Soha Osama Hassanin
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11585, Egypt
| | - Ghada E Ahmed
- Canal Higher Institute for Engineering and Technology- Suez, Egypt
| | - Nirvana A Gohar
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
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8
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Furrer-Matcau C, Sieber C, Lehnick D, Brand CU, Hug B. Cutaneous adverse events due to checkpoint inhibitors - a retrospective analysis at a tertiary referral hospital in Switzerland 2019-2022. Front Oncol 2024; 14:1485594. [PMID: 39703836 PMCID: PMC11655322 DOI: 10.3389/fonc.2024.1485594] [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: 08/24/2024] [Accepted: 11/19/2024] [Indexed: 12/21/2024] Open
Abstract
Introduction Checkpoint inhibitors are increasingly important in anti-cancer treatment. Therefore, knowledge of immune-related cutaneous adverse events (ir-cAE) is crucial for therapy management and continuation. Objective The study aimed to analyze the incidence of cutaneous adverse events caused by checkpoint inhibitor therapy, including their clinical presentation, management, and impact on further treatment. Methods This is a descriptive, monocentric retrospective study that uses data from the electronic health record system at a tertiary referral hospital in Central Switzerland from September 2019 to September 2022. The electronic health records of patients who received a therapy with checkpoint inhibitors were examined for age, sex, type of immunotherapy, time to occurrence of ir-cAEs, characteristics of the ir-cAEs, the treatment approach, and the continuation or cessation of the therapy due to ir-cAEs. Results Out of 431 patients, for 131 patients (30.4%) at least one ir-cAE event was documented. In particular, 109 (25.3%) experienced pruritus and 61 (14.2%) showed a maculopapular exanthema. The severity of the ir-cAE was mild in 88 patients (67.2% out of those with ir-cAEs). Ir-cAE were observed in 10 out of 20 patients (50%) treated with ipilimumab/nivolumab and in 15 out of 24 (62.5%) treated with durvalumab. In 15 patients (3.5%), checkpoint inhibitor therapy had to be discontinued due to cutaneous side effects. Conclusions This study showed that approximately one third of the patients experienced ir-cAEs. The most frequently observed ir-cAEs were pruritus, maculopapular exanthema and xerosis cutis. In general, the dermatological manifestations are mild and responsive to topical treatment or self-limiting with no requirement for treatment interruption.
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Affiliation(s)
- Clara Furrer-Matcau
- Dermatology and Allergology, Cantonal Hospital Lucerne, Lucerne, Switzerland
| | - Chloé Sieber
- Biostatistics and Methodology, Clinical Trials Unit Central Switzerland, Lucerne, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Dirk Lehnick
- Biostatistics and Methodology, Clinical Trials Unit Central Switzerland, Lucerne, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Christoph Urs Brand
- Dermatology and Allergology, Cantonal Hospital Lucerne, Lucerne, Switzerland
| | - Balthasar Hug
- Department of Medicine, Cantonal Hospital Lucerne, Lucerne, Switzerland
- Community Medicine, Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
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Russano F, Rastrelli M, Dall'Olmo L, Del Fiore P, Gianesini C, Vecchiato A, Mazza M, Tropea S, Mocellin S. Therapeutic Treatment Options for In-Transit Metastases from Melanoma. Cancers (Basel) 2024; 16:3065. [PMID: 39272923 PMCID: PMC11394241 DOI: 10.3390/cancers16173065] [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: 08/08/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
In-transit metastases (ITM) in melanoma present a significant therapeutic challenge due to their advanced stage and complex clinical nature. From traditional management with surgical resection, ITM treatment has evolved with the advent of systemic therapies such as immune checkpoint inhibitors and targeted therapies, which have markedly improved survival outcomes. This study aims to review and highlight the efficacy of both systemic and locoregional treatment approaches for ITM. Methods include a comprehensive review of clinical studies examining the impact of treatments like immune checkpoint inhibitors, targeted therapies, Isolated Limb Perfusion, and electrochemotherapy. The results indicate that combining systemic therapies with locoregional treatments enhances both local disease control and overall survival rates. The introduction of modern immunotherapies has not diminished the effectiveness of locoregional therapies but rather improved patient outcomes when used in conjunction. The conclusions emphasize that a multidisciplinary approach integrating systemic and locoregional therapies offers a promising strategy for optimizing the management of ITM in melanoma patients. This integrated treatment model not only improves survival rates but also enhances the quality of life for patients, suggesting a shift in standard care practices toward more comprehensive therapeutic regimens.
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Affiliation(s)
- Francesco Russano
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Marco Rastrelli
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy
| | - Luigi Dall'Olmo
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy
| | - Paolo Del Fiore
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Carlomaria Gianesini
- Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy
| | - Antonella Vecchiato
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Marcodomenico Mazza
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Saveria Tropea
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Simone Mocellin
- Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, 35128 Padova, Italy
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10
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Wu X, Feng N, Wang C, Jiang H, Guo Z. Small molecule inhibitors as adjuvants in cancer immunotherapy: enhancing efficacy and overcoming resistance. Front Immunol 2024; 15:1444452. [PMID: 39161771 PMCID: PMC11330769 DOI: 10.3389/fimmu.2024.1444452] [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: 06/14/2024] [Accepted: 07/22/2024] [Indexed: 08/21/2024] Open
Abstract
Adjuvant therapy is essential in cancer treatment to enhance primary treatment effectiveness, reduce adverse effects, and prevent recurrence. Small molecule inhibitors as adjuvants in cancer immunotherapy aim to harness their immunomodulatory properties to optimize treatment outcomes. By modulating the tumor microenvironment, enhancing immune cell function, and increasing tumor sensitivity to immunotherapy, small molecule inhibitors have the potential to improve patient responses. This review discusses the evolving use of small molecule inhibitors as adjuvants in cancer treatment, highlighting their role in enhancing the efficacy of immunotherapy and the opportunities for advancing cancer therapies in the future.
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Affiliation(s)
- Xiaolin Wu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nuan Feng
- Department of Nutrition, Peking University People’s Hospital, Qingdao, China
- Women and Children’s Hospital, Qingdao University, Qingdao, China
| | - Chao Wang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Hongfei Jiang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Zhu Guo
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- Department of Spinal Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
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11
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Winter RC, Amghar M, Wacker AS, Bakos G, Taş H, Roscher M, Kelly JM, Benešová-Schäfer M. Future Treatment Strategies for Cancer Patients Combining Targeted Alpha Therapy with Pillars of Cancer Treatment: External Beam Radiation Therapy, Checkpoint Inhibition Immunotherapy, Cytostatic Chemotherapy, and Brachytherapy. Pharmaceuticals (Basel) 2024; 17:1031. [PMID: 39204136 PMCID: PMC11359268 DOI: 10.3390/ph17081031] [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: 06/12/2024] [Revised: 07/22/2024] [Accepted: 07/25/2024] [Indexed: 09/03/2024] Open
Abstract
Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients with advanced metastatic disease that has become resistant to other treatments. Yet, in many cases, more sophisticated strategies are needed to stall disease progression and overcome resistance to TαT. The combination of two or more therapies which have historically been used as stand-alone treatments is an approach that has been pursued in recent years. This review aims to provide an overview on TαT and the four main pillars of therapeutic strategies in cancer management, namely external beam radiation therapy (EBRT), immunotherapy with checkpoint inhibitors (ICI), cytostatic chemotherapy (CCT), and brachytherapy (BT), and to discuss their potential use in combination with TαT. A brief description of each therapy is followed by a review of known biological aspects and state-of-the-art treatment practices. The emphasis, however, is given to the motivation for combination with TαT as well as the pre-clinical and clinical studies conducted to date.
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Affiliation(s)
- Ruth Christine Winter
- Research Group Molecular Biology of Systemic Radiotherapy/Translational Radiotheranostics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; (R.C.W.); (M.A.); (G.B.); (H.T.)
| | - Mariam Amghar
- Research Group Molecular Biology of Systemic Radiotherapy/Translational Radiotheranostics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; (R.C.W.); (M.A.); (G.B.); (H.T.)
| | - Anja S. Wacker
- Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA; (A.S.W.); (J.M.K.)
| | - Gábor Bakos
- Research Group Molecular Biology of Systemic Radiotherapy/Translational Radiotheranostics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; (R.C.W.); (M.A.); (G.B.); (H.T.)
| | - Harun Taş
- Research Group Molecular Biology of Systemic Radiotherapy/Translational Radiotheranostics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; (R.C.W.); (M.A.); (G.B.); (H.T.)
| | - Mareike Roscher
- Service Unit for Radiopharmaceuticals and Preclinical Studies, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;
| | - James M. Kelly
- Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA; (A.S.W.); (J.M.K.)
| | - Martina Benešová-Schäfer
- Research Group Molecular Biology of Systemic Radiotherapy/Translational Radiotheranostics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; (R.C.W.); (M.A.); (G.B.); (H.T.)
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12
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Shajari N, Baradaran B, Tohidkia MR, Nasiri H, Sepehri M, Setayesh S, Aghebati-Maleki L. Advancements in Melanoma Therapies: From Surgery to Immunotherapy. Curr Treat Options Oncol 2024; 25:1073-1088. [PMID: 39066854 DOI: 10.1007/s11864-024-01239-8] [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: 06/14/2024] [Indexed: 07/30/2024]
Abstract
OPINION STATEMENT Melanoma is defined as the most aggressive and deadly form of skin cancer. The treatment of melanoma depends on the disease stage, tumor location, and extent of its spread from its point of origin. Melanoma treatment has made significant advances, notably in the context of targeted and immunotherapies. Surgical resection is the main therapeutic option for earlystage melanoma, and it provides favourable outcomes. With disease metastasis, systemic treatments such as immunotherapy and targeted therapy become increasingly important. The identification of mutations that lead to melanoma has influenced treatment strategies. Targeted therapies focusing on these mutations offer improved response rates and fewer toxicities than conventional chemotherapy. Furthermore, developing immunotherapies, including checkpoint inhibitors and tumor-infiltrating lymphocyte (TIL) therapies, has demonstrated encouraging outcomes in effectively combating cancer cells. These therapeutic agents demonstrate superior effectiveness and a more tolerable side-effect profile, improving the quality of life for patients receiving treatment. The future of melanoma treatment may involve a multimodal approach consisting of a combination of surgery, targeted therapy, and immunotherapy adapted to each patient's profile. This approach may improve survival rates and health outcomes.
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Affiliation(s)
- Neda Shajari
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Tohidkia
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Nasiri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Sepehri
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Setayesh
- Department of Pathology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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13
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Pluim D, Buitelaar P, de Jong KAM, Rosing H, Brandsma D, Huitema ADR, Beijnen JH. ELISA assay for the quantification of ipilimumab in human serum, plasma, milk, and cerebrospinal fluid. J Pharm Biomed Anal 2024; 245:116140. [PMID: 38701533 DOI: 10.1016/j.jpba.2024.116140] [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: 02/22/2024] [Revised: 04/02/2024] [Accepted: 04/06/2024] [Indexed: 05/05/2024]
Abstract
Ipilimumab is an immune checkpoint inhibitor of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Ipilimumab has become part of the standard of care for different types of cancer. The efficacy of these treatments is limited due to immune-related toxicity and high economic costs. Dose rationalization studies based on pharmacokinetic data may help to address these limitations. For this purpose, more sensitive analytical methods are needed. We report the development and validation of the first enzyme-linked immunosorbent assay (ELISA) for sensitive determination of ipilimumab concentrations in human serum, plasma, cerebrospinal fluid (CSF), and milk. Our assay is based on the specific capture of ipilimumab by immobilized CTLA-4. The lower limit of quantifications of ipilimumab in serum, plasma, and milk are 50 ng/mL and 10 ng/mL in CSF. The ELISA method showed long-term storage stability for at least one year at -80°C and was successfully cross-validated with ultraperformance liquid chromatography coupled with tandem mass spectrometry. The ELISA method is reliable, relatively inexpensive, and can be used in serum, plasma, CSF, and milk from patients treated with ipilimumab, as evidenced by the analysis of real clinical samples.
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Affiliation(s)
- Dick Pluim
- Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Pauline Buitelaar
- Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Karen A M de Jong
- Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hilde Rosing
- Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Dieta Brandsma
- Department of Neuro-oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Alwin D R Huitema
- Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Jos H Beijnen
- Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
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14
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Guan X, Guo H, Guo Y, Han Q, Li Z, Zhang C. Perforin 1 in Cancer: Mechanisms, Therapy, and Outlook. Biomolecules 2024; 14:910. [PMID: 39199299 PMCID: PMC11352983 DOI: 10.3390/biom14080910] [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: 06/13/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/01/2024] Open
Abstract
PRF1 (perforin 1) is a key cytotoxic molecule that plays a crucial role in the killing function of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Recent studies have focused on PRF1's role in cancer development, progression, and prognosis. Studies have shown that aberrant PRF1 expression has a significant role to play in cancer development and progression. In some cancers, high expression of the PRF1 gene is associated with a better prognosis for patients, possibly because it helps enhance the body's immune response to tumors. However, some studies have also shown that the absence of PRF1 may make it easier for tumors to evade the body's immune surveillance, thus affecting patient survival. Furthermore, recent studies have explored therapeutic strategies based on PRF1, such as enhancing the ability of immune cells to kill cancer cells by boosting PRF1 activity. In addition, they have improved the efficacy of immunotherapy by modulating its expression to enhance the effectiveness of the treatment. Based on these findings, PRF1 may be a valuable biomarker both for the treatment of cancer and for its prognosis in the future. To conclude, PRF1 has an important biological function and has clinical potential for the treatment of cancer, which indicates that it deserves more research and development in the future.
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Affiliation(s)
- Xiaoya Guan
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China; (H.G.); (Y.G.); (Q.H.); (Z.L.)
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Huina Guo
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China; (H.G.); (Y.G.); (Q.H.); (Z.L.)
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Yujia Guo
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China; (H.G.); (Y.G.); (Q.H.); (Z.L.)
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Qi Han
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China; (H.G.); (Y.G.); (Q.H.); (Z.L.)
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Zhongxun Li
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China; (H.G.); (Y.G.); (Q.H.); (Z.L.)
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Chunming Zhang
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China; (H.G.); (Y.G.); (Q.H.); (Z.L.)
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, China
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan 030001, China
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15
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Jaing TH, Wang YL, Chiu CC. Immune Checkpoint Inhibitors for Pediatric Cancers: Is It Still a Stalemate? Pharmaceuticals (Basel) 2024; 17:991. [PMID: 39204096 PMCID: PMC11357301 DOI: 10.3390/ph17080991] [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: 05/18/2024] [Revised: 07/11/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024] Open
Abstract
The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body's natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.
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Affiliation(s)
- Tang-Her Jaing
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| | - Yi-Lun Wang
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| | - Chia-Chi Chiu
- Division of Nursing, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
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16
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Garcia A, Mathew SO. Racial/Ethnic Disparities and Immunotherapeutic Advances in the Treatment of Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2446. [PMID: 39001508 PMCID: PMC11240753 DOI: 10.3390/cancers16132446] [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: 05/24/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the leading causes of death among many associated liver diseases. Various conventional strategies have been utilized for treatment, ranging from invasive surgeries and liver transplants to radiation therapy, but fail due to advanced disease progression, late screening/staging, and the various etiologies of HCC. This is especially evident within racially distinct populations, where incidence rates are higher and treatment outcomes are worse for racial/ethnic minorities than their Caucasian counterparts. However, with the rapid development of genetic engineering and molecular and synthetic biology, many novel strategies have presented promising results and have provided potential treatment options. In this review, we summarize past treatments, how they have shaped current treatments, and potential treatment strategies for HCC that may prove more effective in the future.
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Affiliation(s)
- Alexsis Garcia
- Department of Microbiology, Immunology & Genetics, UNT Health Science Center, Fort Worth, TX 76107, USA
| | - Stephen O Mathew
- Department of Microbiology, Immunology & Genetics, UNT Health Science Center, Fort Worth, TX 76107, USA
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17
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Yang M, Cui M, Sun Y, Liu S, Jiang W. Mechanisms, combination therapy, and biomarkers in cancer immunotherapy resistance. Cell Commun Signal 2024; 22:338. [PMID: 38898505 PMCID: PMC11186190 DOI: 10.1186/s12964-024-01711-w] [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: 03/15/2024] [Accepted: 06/10/2024] [Indexed: 06/21/2024] Open
Abstract
Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.
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Affiliation(s)
- Manshi Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Yang Sun
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, China.
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18
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Abdelrahim M, Esmail A, Divatia MK, Xu J, Kodali S, Victor DW, Brombosz E, Connor AA, Saharia A, Elaileh A, Kaseb AO, Ghobrial RM. Utilization of Immunotherapy as a Neoadjuvant Therapy for Liver Transplant Recipients with Hepatocellular Carcinoma. J Clin Med 2024; 13:3068. [PMID: 38892779 PMCID: PMC11172993 DOI: 10.3390/jcm13113068] [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: 04/03/2024] [Revised: 05/09/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59-64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT.
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Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston Meth-Odist Hospital, Houston, TX 77030, USA; (A.E.)
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston Meth-Odist Hospital, Houston, TX 77030, USA; (A.E.)
| | - Mukul K. Divatia
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Jiaqiong Xu
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston Meth-Odist Hospital, Houston, TX 77030, USA; (A.E.)
| | - Sudha Kodali
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Lynda K. and David M. Underwood Center for Digestive Disorders, Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - David W. Victor
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Lynda K. and David M. Underwood Center for Digestive Disorders, Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Elizabeth Brombosz
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ashton A. Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
| | - Ashish Saharia
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
| | - Ahmed Elaileh
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ahmed O. Kaseb
- Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rafik Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
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19
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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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20
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Knoedler L, Huelsboemer L, Hollmann K, Alfertshofer M, Herfeld K, Hosseini H, Boroumand S, Stoegner VA, Safi AF, Perl M, Knoedler S, Pomahac B, Kauke-Navarro M. From standard therapies to monoclonal antibodies and immune checkpoint inhibitors - an update for reconstructive surgeons on common oncological cases. Front Immunol 2024; 15:1276306. [PMID: 38715609 PMCID: PMC11074450 DOI: 10.3389/fimmu.2024.1276306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 04/05/2024] [Indexed: 05/23/2024] Open
Abstract
Malignancies represent a persisting worldwide health burden. Tumor treatment is commonly based on surgical and/or non-surgical therapies. In the recent decade, novel non-surgical treatment strategies involving monoclonal antibodies (mAB) and immune checkpoint inhibitors (ICI) have been successfully incorporated into standard treatment algorithms. Such emerging therapy concepts have demonstrated improved complete remission rates and prolonged progression-free survival compared to conventional chemotherapies. However, the in-toto surgical tumor resection followed by reconstructive surgery oftentimes remains the only curative therapy. Breast cancer (BC), skin cancer (SC), head and neck cancer (HNC), and sarcoma amongst other cancer entities commonly require reconstructive surgery to restore form, aesthetics, and functionality. Understanding the basic principles, strengths, and limitations of mAB and ICI as (neo-) adjuvant therapies and treatment alternatives for resectable or unresectable tumors is paramount for optimized surgical therapy planning. Yet, there is a scarcity of studies that condense the current body of literature on mAB and ICI for BC, SC, HNC, and sarcoma. This knowledge gap may result in suboptimal treatment planning, ultimately impairing patient outcomes. Herein, we aim to summarize the current translational endeavors focusing on mAB and ICI. This line of research may serve as an evidence-based fundament to guide targeted therapy and optimize interdisciplinary anti-cancer strategies.
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Affiliation(s)
- Leonard Knoedler
- Department of Plastic, Hand, and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Lioba Huelsboemer
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Katharina Hollmann
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Faculty of Medicine, University of Wuerzbuerg, Wuerzburg, Germany
| | - Michael Alfertshofer
- Division of Hand, Plastic and Aesthetic Surgery, Ludwig-Maximilians University Munich, Munich, Germany
| | - Konstantin Herfeld
- Department of Internal Medicine III (Oncology and Haematology), University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Helia Hosseini
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Sam Boroumand
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Viola A. Stoegner
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
| | - Ali-Farid Safi
- Craniologicum, Center for Cranio-Maxillo-Facial Surgery, Bern, Switzerland
- Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Markus Perl
- Department of Internal Medicine III (Oncology and Haematology), University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Samuel Knoedler
- Department of Plastic, Hand, and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Bohdan Pomahac
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Martin Kauke-Navarro
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
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21
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Akbulut Z, Aru B, Aydın F, Yanıkkaya Demirel G. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Front Immunol 2024; 15:1379622. [PMID: 38638433 PMCID: PMC11024234 DOI: 10.3389/fimmu.2024.1379622] [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: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/20/2024] Open
Abstract
Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.
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Affiliation(s)
- Zeynep Akbulut
- Cancer and Stem Cell Research Center, Maltepe University, Istanbul, Türkiye
- Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, Istanbul, Türkiye
| | - Başak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Furkan Aydın
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
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22
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Uchi H. Optimal strategy in managing advanced melanoma. J Dermatol 2024; 51:324-334. [PMID: 38087810 PMCID: PMC11483965 DOI: 10.1111/1346-8138.17068] [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: 09/30/2023] [Revised: 11/01/2023] [Accepted: 11/20/2023] [Indexed: 03/05/2024]
Abstract
The advent of immune checkpoint inhibitors and combination therapy with BRAF inhibitors and MEK inhibitors has dramatically improved the prognosis of advanced melanoma. However, since acral melanoma and mucosal melanoma, which are rare in Western countries but are major subtypes of melanoma in East Asia, including Japan, have a low frequency of BRAF mutations, there are currently no treatment options other than immune checkpoint inhibitors in most such cases. Furthermore, owing to a lower tumor mutation burden, immune checkpoint inhibitors are less effective in acral and mucosal melanoma than in cutaneous melanoma. The aim of this review was to summarize the current status and future prospects for the treatment of advanced melanoma, comparing cutaneous melanoma, acral melanoma, and mucosal melanoma.
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Affiliation(s)
- Hiroshi Uchi
- Department of Dermato‐OncologyNational Hospital Organization Kyushu Cancer CenterFukuokaJapan
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23
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Di Giacomo AM, Lahn M, Eggermont AM, Fox B, Ibrahim R, Sharma P, Allison JP, Maio M. The future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role? Eur J Cancer 2024; 198:113501. [PMID: 38169219 DOI: 10.1016/j.ejca.2023.113501] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 12/13/2023] [Indexed: 01/05/2024]
Abstract
The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Anna Maria Di Giacomo
- University of Siena, Siena, Italy; Center for Immuno-Oncology. University Hospital of Siena, Viale Bracci, 16, Siena, Italy; NIBIT Foundation Onlus, Italy
| | - Michael Lahn
- IOnctura SA, Avenue Secheron 15, Geneva, Switzerland
| | - Alexander Mm Eggermont
- Princess Máxima Center and the University Medical Center Utrecht, Heidelberglaan 25, 3584 Utrecht, the Netherlands; Comprehensive Cancer Center Munich of the Technical University Munich and the Ludwig Maximiliaan University, Munich, Germany
| | - Bernard Fox
- Earle A. Chiles Research Institute at the Robert W. Franz Cancer Center, 4805 NE Glisan St. Suite 2N35 Portland, OR 97213, USA
| | - Ramy Ibrahim
- Parker Institute for Cancer Immunotherapy, 1 Letterman Drive, D3500, San Francisco, CA, USA
| | - Padmanee Sharma
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson, 1515 Holcombe Blvd, Houston, Texas 77030, USA
| | - James P Allison
- James P Allison Institute, MD Anderson, 1515 Holcombe Blvd, Texas 77030, USA
| | - Michele Maio
- University of Siena, Siena, Italy; Center for Immuno-Oncology. University Hospital of Siena, Viale Bracci, 16, Siena, Italy; NIBIT Foundation Onlus, Italy.
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24
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Rohatgi N, Rothe M, Mangat PK, Garrett-Mayer E, Meric-Bernstam F, Pisick E, Alese OB, Reynolds CM, Thota R, Vaccaro GM, von Mehren M, Arend RC, Chiu VK, Duvivier HL, Gold PJ, Hack K, Marr AS, Winer A, Grantham GN, Hinshaw DC, Gregory A, Halabi S, Schilsky RL. Nivolumab Plus Ipilimumab in Patients With Solid Tumors With ATM Mutations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. JCO Precis Oncol 2023; 7:e2300279. [PMID: 38039429 DOI: 10.1200/po.23.00279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/24/2023] [Accepted: 09/01/2023] [Indexed: 12/03/2023] Open
Abstract
PURPOSE The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with ATM mutations treated with nivolumab plus ipilimumab are reported. METHODS Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16 weeks duration (SD16+). Low-accruing histology-specific cohorts with ATM mutations treated with nivolumab plus ipilimumab were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated based on a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = .84; α = .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS Twenty-nine patients with 10 tumor types with ATM mutations were enrolled from January 2018 to May 2020. One patient was not evaluable for efficacy. One CR, three PR, and three SD16+ were observed for DC and OR rates of 24% (P = .13; one-sided 90% CI: 14 to 100) and 14% (95% CI: 4 to 32), respectively. The null hypothesis of 15% DC rate was not rejected. Eleven patients had one treatment-related grade 3 adverse event (AE) or serious AE. There were two treatment-related patient deaths including immune-related encephalitis and respiratory failure. CONCLUSION Nivolumab plus ipilimumab did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with ATM mutations.
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Affiliation(s)
| | - Michael Rothe
- American Society of Clinical Oncology, Alexandria, VA
| | - Pam K Mangat
- American Society of Clinical Oncology, Alexandria, VA
| | | | | | | | | | | | | | | | | | - Rebecca C Arend
- O'Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham, AL
| | - Vi K Chiu
- The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, CA
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25
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Zhang J, Wang S, Zhang D, He X, Wang X, Han H, Qin Y. Nanoparticle-based drug delivery systems to enhance cancer immunotherapy in solid tumors. Front Immunol 2023; 14:1230893. [PMID: 37600822 PMCID: PMC10435760 DOI: 10.3389/fimmu.2023.1230893] [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: 05/29/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Immunotherapy has developed rapidly in solid tumors, especially in the areas of blocking inhibitory immune checkpoints and adoptive T-cell transfer for immune regulation. Many patients benefit from immunotherapy. However, the response rate of immunotherapy in the overall population are relatively low, which depends on the characteristics of the tumor and individualized patient differences. Moreover, the occurrence of drug resistance and adverse reactions largely limit the development of immunotherapy. Recently, the emergence of nanodrug delivery systems (NDDS) seems to improve the efficacy of immunotherapy by encapsulating drug carriers in nanoparticles to precisely reach the tumor site with high stability and biocompatibility, prolonging the drug cycle of action and greatly reducing the occurrence of toxic side effects. In this paper, we mainly review the advantages of NDDS and the mechanisms that enhance conventional immunotherapy in solid tumors, and summarize the recent advances in NDDS-based therapeutic strategies, which will provide valuable ideas for the development of novel tumor immunotherapy regimen.
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Affiliation(s)
- Jiaxin Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Siyuan Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Daidi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin He
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xue Wang
- Academy of Medical Science, School of Basic Medical Science, Zhengzhou University, Zhengzhou, China
| | - Huiqiong Han
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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26
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Sausen DG, Shechter O, Gallo ES, Dahari H, Borenstein R. Herpes Simplex Virus, Human Papillomavirus, and Cervical Cancer: Overview, Relationship, and Treatment Implications. Cancers (Basel) 2023; 15:3692. [PMID: 37509353 PMCID: PMC10378257 DOI: 10.3390/cancers15143692] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
There is a significant body of research examining the role of human papillomavirus (HPV) in the pathogenesis of cervical cancer, with a particular emphasis on the oncogenic proteins E5, E6, and E7. What is less well explored, however, is the relationship between cervical cancer and herpes simplex virus (HSV). To date, studies examining the role of HSV in cervical cancer pathogenesis have yielded mixed results. While several experiments have determined that HPV/HSV-2 coinfection results in a higher risk of developing cervical cancer, others have questioned the validity of this association. However, clarifying the potential role of HSV in the pathogenesis of cervical cancer may have significant implications for both the prevention and treatment of this disease. Should this relationship be clarified, treating and preventing HSV could open another avenue with which to prevent cervical cancer. The importance of this is highlighted by the fact that, despite the creation of an effective vaccine against HPV, cervical cancer still impacts 604,000 women and is responsible for 342,000 deaths annually. This review provides an overview of HSV and HPV infections and then delves into the possible links between HPV, HSV, and cervical cancer. It concludes with a summary of preventive measures against and recent treatment advances in cervical cancer.
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Affiliation(s)
- Daniel G. Sausen
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA; (D.G.S.); (O.S.)
| | - Oren Shechter
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501, USA; (D.G.S.); (O.S.)
| | - Elisa S. Gallo
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
| | - Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA;
| | - Ronen Borenstein
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA;
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27
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Pundkar C, Antony F, Kang X, Mishra A, Babu RJ, Chen P, Li F, Suryawanshi A. Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity. Heliyon 2023; 9:e16688. [PMID: 37313143 PMCID: PMC10258387 DOI: 10.1016/j.heliyon.2023.e16688] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/15/2023] Open
Abstract
The aberrant activation of Wnt/β-catenin signaling in tumor cells and immune cells in the tumor microenvironment (TME) promotes malignant transformation, metastasis, immune evasion, and resistance to cancer treatments. The increased Wnt ligand expression in TME activates β-catenin signaling in antigen (Ag)-presenting cells (APCs) and regulates anti-tumor immunity. Previously, we showed that activation of Wnt/β-catenin signaling in dendritic cells (DCs) promotes induction of regulatory T cell responses over anti-tumor CD4+ and CD8+ effector T cell responses and promotes tumor progression. In addition to DCs, tumor-associated macrophages (TAMs) also serve as APCs and regulate anti-tumor immunity. However, the role of β-catenin activation and its effect on TAM immunogenicity in TME is largely undefined. In this study, we investigated whether inhibiting β-catenin in TME-conditioned macrophages promotes immunogenicity. Using nanoparticle formulation of XAV939 (XAV-Np), a tankyrase inhibitor that promotes β-catenin degradation, we performed in vitro macrophage co-culture assays with melanoma cells (MC) or melanoma cell supernatants (MCS) to investigate the effect on macrophage immunogenicity. We show that XAV-Np-treatment of macrophages conditioned with MC or MCS significantly upregulates the cell surface expression of CD80 and CD86 and suppresses the expression of PD-L1 and CD206 compared to MC or MCS-conditioned macrophages treated with control nanoparticle (Con-Np). Further, XAV-Np-treated macrophages conditioned with MC or MCS significantly increased IL-6 and TNF-α production, with reduced IL-10 production compared to Con-Np-treated macrophages. Moreover, the co-culture of MC and XAV-Np-treated macrophages with T cells resulted in increased CD8+ T cell proliferation compared to Con-Np-treated macrophages. These data suggest that targeted β-catenin inhibition in TAMs represents a promising therapeutic approach to promote anti-tumor immunity.
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Affiliation(s)
- Chetan Pundkar
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Ferrin Antony
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Xuejia Kang
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA
| | - Amarjit Mishra
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - R. Jayachandra Babu
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Pengyu Chen
- Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA
| | - Feng Li
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Amol Suryawanshi
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
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28
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Valerio TI, Furrer CL, Sadeghipour N, Patrock SJX, Tillery SA, Hoover AR, Liu K, Chen WR. Immune modulations of the tumor microenvironment in response to phototherapy. JOURNAL OF INNOVATIVE OPTICAL HEALTH SCIENCES 2023; 16:2330007. [PMID: 38550850 PMCID: PMC10976517 DOI: 10.1142/s1793545823300070] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/01/2024]
Abstract
The tumor microenvironment (TME) promotes pro-tumor and anti-inflammatory metabolisms and suppresses the host immune system. It prevents immune cells from fighting against cancer effectively, resulting in limited efficacy of many current cancer treatment modalities. Different therapies aim to overcome the immunosuppressive TME by combining various approaches to synergize their effects for enhanced anti-tumor activity and augmented stimulation of the immune system. Immunotherapy has become a major therapeutic strategy because it unleashes the power of the immune system by activating, enhancing, and directing immune responses to prevent, control, and eliminate cancer. Phototherapy uses light irradiation to induce tumor cell death through photothermal, photochemical, and photo-immunological interactions. Phototherapy induces tumor immunogenic cell death, which is a precursor and enhancer for anti-tumor immunity. However, phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses. Phototherapy can be combined with immunotherapy to improve the tumoricidal effect by killing target tumor cells, enhancing immune cell infiltration in tumors, and rewiring pathways in the TME from anti-inflammatory to pro-inflammatory. Phototherapy-enhanced immunotherapy triggers effective cooperation between innate and adaptive immunities, specifically targeting the tumor cells, whether they are localized or distant. Herein, the successes and limitations of phototherapy combined with other cancer treatment modalities will be discussed. Specifically, we will review the synergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immunosuppressive TME. Overall, phototherapy, in combination with other therapeutic modalities, can establish anti-tumor pro-inflammatory phenotypes in activated tumor-infiltrating T cells and B cells and activate systemic anti-tumor immune responses.
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Affiliation(s)
- Trisha I. Valerio
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Coline L. Furrer
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Negar Sadeghipour
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
- School of Electrical and Computer Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Sophia-Joy X. Patrock
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Sayre A. Tillery
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Ashley R. Hoover
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Kaili Liu
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
| | - Wei R. Chen
- Stephenson School of Biomedical Engineering University of Oklahoma, Norman, Oklahoma 73019, USA
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29
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Cole K, Al-Kadhimi Z, Talmadge JE. Highlights into historical and current immune interventions for cancer. Int Immunopharmacol 2023; 117:109882. [PMID: 36848790 PMCID: PMC10355273 DOI: 10.1016/j.intimp.2023.109882] [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: 12/30/2022] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 03/01/2023]
Abstract
Immunotherapy is an additional pillar when combined with traditional standards of care such as chemotherapy, radiotherapy, and surgery for cancer patients. It has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapies, including adoptive cellular therapy (ACT) and checkpoint inhibitors (CPIs), can induce durable clinical responses. However, their efficacies vary, and only subsets of cancer patients benefit from their use. In this review, we address three goals: to provide insight into the history of these approaches, broaden our understanding of immune interventions, and discuss current and future approaches. We highlight how cancer immunotherapy has evolved and discuss how personalization of immune intervention may address present limitations. Cancer immunotherapy is considered a recent medical achievement and in 2013 was selected as the "Breakthrough of the Year" by Science. While the breadth of immunotherapeutics has been rapidly expanding, to include the use of chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitor (ICI) therapy, immunotherapy dates back over 3000 years. The expansive history of immunotherapy, and related observations, have resulted in several approved immune therapeutics beyond the recent emphasis on CAR-T and ICI therapies. In addition to other classical forms of immune intervention, including human papillomavirus (HPV), hepatitis B, and the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) tuberculosis vaccines, immunotherapies have had a broad and durable impact on cancer therapy and prevention. One classic example of immunotherapy was identified in 1976 with the use of intravesical administration of BCG in patients with bladder cancer; resulting in a 70 % eradication rate and is now standard of care. However, a greater impact from the use of immunotherapy is documented by the prevention of HPV infections that are responsible for 98 % of cervical cancer cases. In 2020, the World Health Organization (WHO) estimated that 341,831 women died from cervical cancer [1]. However, administration of a single dose of a bivalent HPV vaccine was shown to be 97.5 % effective in preventing HPV infections. These vaccines not only prevent cervical squamous cell carcinoma and adenocarcinoma, but also oropharyngeal, anal, vulvar, vaginal, and penile squamous cell carcinomas. The breadth, response and durability of these vaccines can be contrasted with CAR-T-cell therapies, which have significant barriers to their widespread use including logistics, manufacturing limitations, toxicity concerns, financial burden and lasting remissions observed in only 30 to 40 % of responding patients. Another, recent immunotherapy focus are ICIs. ICIs are a class of antibodies that can increase the immune responses against cancer cells in patients. However, ICIs are only effective against tumors with a high mutational burden and are associated with a broad spectrum of toxicities requiring interruption of administration and/or administration corticosteroids; both of which limit immune therapy. In summary, immune therapeutics have a broad impact worldwide, utilizing numerous mechanisms of action and when considered in their totality are more effective against a broader range of tumors than initially considered. These new cancer interventions have tremendous potential notability when multiple mechanisms of immune intervention are combined as well as with standard of care modalities.
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Affiliation(s)
- Kathryn Cole
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Zaid Al-Kadhimi
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - James E Talmadge
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Nemovi K, Jamali A, Matinpour K, Dasanu CA. Widespread vitiligo and poliosis following ipilimumab-nivolumab combination therapy. J Oncol Pharm Pract 2023:10781552231154460. [PMID: 36785936 DOI: 10.1177/10781552231154460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
INTRODUCTION Combined immune checkpoint inhibitor therapy has been successfully used in the treatment of several malignancies. Adverse effects with the combination therapy may be more severe than the ones seen with single immune checkpoint inhibitors. CASE PRESENTATION We report a unique case of a 59-year-old man of dark skin complexion who underwent treatment with intravenous ipilimumab-nivolumab every 3 weeks for metastatic malignant melanoma. After three cycles of this therapy, he developed extensive skin depigmentation that within 6 weeks, affected nearly the entire skin surface, along with progressive poliosis. MANAGEMENT AND OUTCOME Ipilimumab-nivolumab therapy was subsequently discontinued due to grade 3 enterocolitis requiring high-dose steroids and intravenous infliximab. About six months later, imaging studies showed a relapse of malignant melanoma. At that juncture, vitiligo affected the total body surface area, resembling albinism, along with near-total poliosis and significant photosensitivity. Pembrolizumab was tried but had to be stopped after three cycles due to the reoccurrence of grade 3 enterocolitis. Progression of malignant melanoma with new brain, lung, liver, subcutaneous, and colonic metastases led to the patient's demise. CONCLUSION We report a unique case of severe vitiligo and poliosis that involved total body surface area in a Caucasian man with dark complexion, resembling albinism. Further studies are warranted to evaluate the severity of dermatologic side effects with combination immune checkpoint inhibitor therapy.
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Affiliation(s)
- Khashayar Nemovi
- Department of Internal Medicine, 541618Eisenhower Health, Rancho Mirage, CA, USA
| | - Arsia Jamali
- Department of Internal Medicine, 541618Eisenhower Health, Rancho Mirage, CA, USA
| | - Keyan Matinpour
- Department of Dermatology, 541618Eisenhower Health, Rancho Mirage, CA, USA
| | - Constantin A Dasanu
- Department of Hematology and Oncology, Eisenhower Lucy Curci Cancer Center, Rancho Mirage, CA, USA.,Department of Hematology and Oncology, UC San Diego Health System, San Diego, CA, USA
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Funagura N, Fukushima S, Inoue T. Ipilimumab-related uveitis and refractory hypotony with a flat chamber in a trabeculectomized eye with exfoliation glaucoma: A case report. Am J Ophthalmol Case Rep 2023; 29:101807. [PMID: 36714018 PMCID: PMC9876775 DOI: 10.1016/j.ajoc.2023.101807] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 01/06/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
Purpose Ipilimumab is an immune checkpoint inhibitor that occasionally causes ophthalmic immune-related adverse events (irAEs) such as dry eye, uveitis, and episcleritis. We report a case of ipilimumab-related uveitis and refractory hypotony with a flat anterior chamber (AC) in a trabeculectomized eye with exfoliation glaucoma. Observation A 69-year-old man with a history of cataract surgery and trabeculectomy for exfoliation glaucoma in the right eye presented with blurred vision at 2 months after initiation of ipilimumab for metastatic malignant melanoma (day 0). Although no ophthalmic irAEs were observed at the first visit, he developed iritis, vitreous opacity, and choroidal detachment by day 18.As a result of the irAEs, the scheduled course of ipilimumab was canceled and he was instead treated with corticosteroids (eye drops and systemic). The symptoms progressed, and on day 32 visual acuity was light perception, with a flat AC, hypotony maculopathy, and severe choroidal detachment in the right eye. The patient received two AC formations with a viscoelastic substance, but the flat AC and hypotony recurred. Because the effects of the surgeries were temporary, high doses of corticosteroids were administered. AC depth, anterior uveitis, intraocular pressure, and choroidal detachment resolved by day 91. Conclusions Ophthalmologists and oncologists should be aware of the rare but severe irAEs, and careful follow-up is required for ophthalmic irAEs caused by ipilimumab, especially in cases with a history of glaucoma surgery.
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Affiliation(s)
- Naofumi Funagura
- Department of Ophthalmology, Faculty of Life Science, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan,Corresponding author. Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan.
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery, Faculty of Life Science, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
| | - Toshihiro Inoue
- Department of Ophthalmology, Faculty of Life Science, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan
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Zhang J, Han H, Wang L, Wang W, Yang M, Qin Y. Overcoming the therapeutic resistance of hepatomas by targeting the tumor microenvironment. Front Oncol 2022; 12:988956. [DOI: 10.3389/fonc.2022.988956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 11/01/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is the third leading cause of cancer-related mortality worldwide. Multifactorial drug resistance is regarded as the major cause of treatment failure in HCC. Accumulating evidence shows that the constituents of the tumor microenvironment (TME), including cancer-associated fibroblasts, tumor vasculature, immune cells, physical factors, cytokines, and exosomes may explain the therapeutic resistance mechanisms in HCC. In recent years, anti-angiogenic drugs and immune checkpoint inhibitors have shown satisfactory results in HCC patients. However, due to enhanced communication between the tumor and TME, the effect of heterogeneity of the microenvironment on therapeutic resistance is particularly complicated, which suggests a more challenging research direction. In addition, it has been reported that the three-dimensional (3D) organoid model derived from patient biopsies is more intuitive to fully understand the role of the TME in acquired resistance. Therefore, in this review, we have focused not only on the mechanisms and targets of therapeutic resistance related to the contents of the TME in HCC but also provide a comprehensive description of 3D models and how they contribute to the exploration of HCC therapies.
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Zaman R, Islam RA, Chowdhury EH. Evolving therapeutic proteins to precisely kill cancer cells. J Control Release 2022; 351:779-804. [DOI: 10.1016/j.jconrel.2022.09.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 10/31/2022]
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Obeidat A, Silangcruz K, Kozai L, Wien E, Fujiwara Y, Nishimura Y. Clinical Characteristics and Outcomes of Gastritis Associated With Immune Checkpoint Inhibitors: Scoping Review. J Immunother 2022; 45:363-369. [PMID: 35972801 DOI: 10.1097/cji.0000000000000435] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/30/2022] [Indexed: 11/25/2022]
Abstract
Among immune-related adverse events associated with immune checkpoint inhibitors, immune-mediated gastritis (IMG) has been rarely described in the literature and has not yet been well characterized. This scoping review aimed to characterize IMG in terms of precipitating agents, clinical presentations, and prognosis. After the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "gastritis," "immune checkpoint inhibitor," and "immune-related adverse event" from their inception to December 28, 2021. Twenty-two articles, including 5 observational studies and 17 case reports and case series, were included. Nivolumab, pembrolizumab, and combination therapy with those and cytotoxic T-lymphocyte-associated antigen-4 inhibitor (ipilimumab) were commonly used in those with IMG. 59.8% had epigastric pain, and 50% had erosive gastritis. 87.5% had Common Terminology Criteria for Adverse Events (CTCAE) grade 3 gastritis, and 91.2% received corticosteroids. Recurrence was noted in 16.7%, and only 1 expiration was noted. 4.3% had positive helicobacter pylori and cytomegalovirus from the gastric specimen. Similar to immune-related colitis, patients with IMG may have a favorable prognosis with a better response to immune checkpoint inhibitors if treated appropriately. The diagnosis of IMG is made by exclusion, and a thorough workup is necessary to rule out concurrent helicobacter pylori and cytomegalovirus involvement. Further studies are critical for a better understanding of this complication.
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Affiliation(s)
- Adham Obeidat
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Krixie Silangcruz
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Landon Kozai
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Eric Wien
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
| | - Yu Fujiwara
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY
| | - Yoshito Nishimura
- Department of Medicine, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI
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36
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Jiang S, Fagman JB, Ma Y, Liu J, Vihav C, Engstrom C, Liu B, Chen C. A comprehensive review of pancreatic cancer and its therapeutic challenges. Aging (Albany NY) 2022; 14:7635-7649. [PMID: 36173644 PMCID: PMC9550249 DOI: 10.18632/aging.204310] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 09/17/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic cancer is a devastating and lethal human malignancy with no curable chemo-treatments available thus far. More than 90% of pancreatic tumors are formed from ductal epithelium as pancreatic ductal adenocarcinoma (PDAC), which often accompany with the expression of mutant K-ras. The incidences of pancreatic cancer are expected to increase rapidly worldwide in the near future, due to environmental pollution, obesity epidemics and etc. The dismal prognosis of this malignancy is contributed to its susceptibility to tumor micro-metastasis from inception and the lack of methods to detect precursor lesions at very early stages of the onset until clinical symptoms occur. In recent years, basic and clinical studies have been making promising progresses for discovering markers to determine the subtypes or stages of this malignancy, which allow effectively implementing personalized therapeutic interventions. The purpose of this review is to discuss the existing knowledge of the molecular mechanisms of pancreatic cancer and the current state of treatment options with the emphasis on targeting therapeutic approaches. The specific focuses are on the molecular mechanisms of the disease, identifications of drug resistance, establishment of immune escaping mechanisms as well as potential of targeting identified pathways in combinations with existing chemo-drugs.
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Affiliation(s)
- Shan Jiang
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
| | - Johan Bourghardt Fagman
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
- Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Yunyun Ma
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
| | - Jian Liu
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
- The First Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Caroline Vihav
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
- Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cecilia Engstrom
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
- Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Beidong Liu
- Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
| | - Changyan Chen
- Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
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Alalawi M, Bakr AS, Reda R, Sadak KT, Nagy M. Late-onset toxicities of monoclonal antibodies in cancer patients. Immunotherapy 2022; 14:1067-1083. [PMID: 35892252 DOI: 10.2217/imt-2022-0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Cancer therapy duration is variable and may take years, adding a new challenge of maintaining the best life quality for cancer survivors. In cancer patients, late-onset toxicities have been reported with monoclonal antibodies and may involve several body organs or systems. They are defined as an autoimmune illnesses that can happen months to years after treatment discontinuation. Late-onset toxicities have become a focus of clinical care and related research. After cancer therapy is completed, the patient should receive longitudinal follow-up to detect these late effects as early as possible. The current review summarizes the recently reported late-onset toxicities of four classes of monoclonal antibodies (anti-CD52, anti-CTLA-4, anti-PD-1 and anti-CD20) with guidance for the diagnostic tools, appropriate management and treatment.
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Affiliation(s)
- Mai Alalawi
- Department of Pharmaceutical Services, Children's Cancer Hospital Egypt, Cairo, 57357, 4260102, Egypt.,Department of Pharmaceutical Sciences, Fakeeh College for Medical Sciences, Jeddah, 23323, Saudi Arabia
| | - Abrar Saeed Bakr
- Department of Pharmaceutical Services, Children's Cancer Hospital Egypt, Cairo, 57357, 4260102, Egypt.,Department of Clinical Pharmacy, Alexandria Vascular Center, Alexandria, 5431118, Egypt
| | - Rowaida Reda
- Department of Pharmaceutical Services, Children's Cancer Hospital Egypt, Cairo, 57357, 4260102, Egypt.,Department of Clinical Pharmacy, Woman Health Hospital, Assiut University, Assiut, 2074020, Egypt
| | - Karim Thomas Sadak
- University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA.,University of Minnesota Masonic Children's Hospital, Minneapolis, MN 55455, USA
| | - Mohamad Nagy
- Department of Pharmaceutical Services, Children's Cancer Hospital Egypt, Cairo, 57357, 4260102, Egypt.,Personalized Medication Management Unit, Children's Cancer Hospital Egypt, Cairo, 57357, 4260102, Egypt
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38
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Chen CH, Yu HS, Yu S. Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article. Curr Oncol 2022; 29:2871-2886. [PMID: 35448208 PMCID: PMC9032875 DOI: 10.3390/curroncol29040234] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/15/2022] [Accepted: 04/15/2022] [Indexed: 12/19/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients.
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Affiliation(s)
- Chieh-Hsun Chen
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Hsin-Su Yu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Sebastian Yu
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Dermatology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 6103)
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Assessing the Future of Solid Tumor Immunotherapy. Biomedicines 2022; 10:biomedicines10030655. [PMID: 35327456 PMCID: PMC8945484 DOI: 10.3390/biomedicines10030655] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
With the advent of cancer immunotherapy, there has been a major improvement in patient’s quality of life and survival. The growth of cancer immunotherapy has dramatically changed our understanding of the basics of cancer biology and has altered the standards of care (surgery, radiotherapy, and chemotherapy) for patients. Cancer immunotherapy has generated significant excitement with the success of chimeric antigen receptor (CAR) T cell therapy in particular. Clinical results using CAR-T for hematological malignancies have led to the approval of four CD19-targeted and one B-cell maturation antigen (BCMA)-targeted cell therapy products by the US Food and Drug Administration (FDA). Also, immune checkpoint inhibitors such as antibodies against Programmed Cell Death-1 (PD-1), Programmed Cell Death Ligand-1 (PD-L1), and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) have shown promising therapeutic outcomes and long-lasting clinical effect in several tumor types and patients who are refractory to other treatments. Despite these promising results, the success of cancer immunotherapy in solid tumors has been limited due to several barriers, which include immunosuppressive tumor microenvironment (TME), inefficient trafficking, and heterogeneity of tumor antigens. This is further compounded by the high intra-tumoral pressure of solid tumors, which presents an additional challenge to successfully delivering treatments to solid tumors. In this review, we will outline and propose specific approaches that may overcome these immunological and physical barriers to improve the outcomes in solid tumor patients receiving immunotherapies.
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Naccache R, Belkouchi Y, Lawrance L, Benatsou B, Hadchiti J, Cournede PH, Ammari S, Talbot H, Lassau N. Prediction of Early Response to Immunotherapy: DCE-US as a New Biomarker. Cancers (Basel) 2022; 14:cancers14051337. [PMID: 35267645 PMCID: PMC8909556 DOI: 10.3390/cancers14051337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Immune checkpoint inhibitors (ICI) have revolutionized cancer care. However, assessing the efficacy of these new molecules with targeted therapeutic responses may induce too much delay when using classical biomarkers derived from morphological imaging (CT). The objective of our study is to propose fast, cost-effective, convenient, and effective biomarkers using the perfusion parameters from dynamic contrast-enhanced ultrasound (DCE-US) for the evaluation of ICI early response. In a population of 63 patients with metastatic cancer eligible for immunotherapy, we demonstrate that a decrease of more than 45% in the area under the perfusion curve (AUC) between baseline and day 21 is significantly associated with better overall survival. Thus, AUC from DCE-US looks to be a promising new biomarker for the early evaluation of response to immunotherapy. Abstract Purpose: The objective of our study is to propose fast, cost-effective, convenient, and effective biomarkers using the perfusion parameters from dynamic contrast-enhanced ultrasound (DCE-US) for the evaluation of immune checkpoint inhibitors (ICI) early response. Methods: The retrospective cohort used in this study included 63 patients with metastatic cancer eligible for immunotherapy. DCE-US was performed at baseline, day 8 (D8), and day 21 (D21) after treatment onset. A tumor perfusion curve was modeled on these three dates, and change in the seven perfusion parameters was measured between baseline, D8, and D21. These perfusion parameters were studied to show the impact of their variation on the overall survival (OS). Results: After the removal of missing or suboptimal DCE-US, the Baseline-D8, the Baseline-D21, and the D8-D21 groups included 37, 53, and 33 patients, respectively. A decrease of more than 45% in the area under the perfusion curve (AUC) between baseline and D21 was significantly associated with better OS (p = 0.0114). A decrease of any amount in the AUC between D8 and D21 was also significantly associated with better OS (p = 0.0370). Conclusion: AUC from DCE-US looks to be a promising new biomarker for fast, effective, and convenient immunotherapy response evaluation.
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Affiliation(s)
- Raphael Naccache
- Department of Imaging, Institut Gustave Roussy, 94800 Villejuif, France; (B.B.); (J.H.); (S.A.); (N.L.)
- Correspondence: (R.N.); (Y.B.)
| | - Younes Belkouchi
- CVN INRIA, CentraleSupelec, Universite Paris-Saclay, 91190 Gif-Sur-Yvette, France;
- Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, BIOMAPS, UMR 1281, Université Paris-Saclay, Inserm, CNRS, CEA, 94800 Villejuif, France;
- Correspondence: (R.N.); (Y.B.)
| | - Littisha Lawrance
- Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, BIOMAPS, UMR 1281, Université Paris-Saclay, Inserm, CNRS, CEA, 94800 Villejuif, France;
| | - Baya Benatsou
- Department of Imaging, Institut Gustave Roussy, 94800 Villejuif, France; (B.B.); (J.H.); (S.A.); (N.L.)
- Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, BIOMAPS, UMR 1281, Université Paris-Saclay, Inserm, CNRS, CEA, 94800 Villejuif, France;
| | - Joya Hadchiti
- Department of Imaging, Institut Gustave Roussy, 94800 Villejuif, France; (B.B.); (J.H.); (S.A.); (N.L.)
| | - Paul-Henry Cournede
- MICS Lab, CentraleSupelec, Universite Paris-Saclay, 91190 Gif-Sur-Yvette, France;
| | - Samy Ammari
- Department of Imaging, Institut Gustave Roussy, 94800 Villejuif, France; (B.B.); (J.H.); (S.A.); (N.L.)
- Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, BIOMAPS, UMR 1281, Université Paris-Saclay, Inserm, CNRS, CEA, 94800 Villejuif, France;
| | - Hugues Talbot
- CVN INRIA, CentraleSupelec, Universite Paris-Saclay, 91190 Gif-Sur-Yvette, France;
| | - Nathalie Lassau
- Department of Imaging, Institut Gustave Roussy, 94800 Villejuif, France; (B.B.); (J.H.); (S.A.); (N.L.)
- Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, BIOMAPS, UMR 1281, Université Paris-Saclay, Inserm, CNRS, CEA, 94800 Villejuif, France;
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Tran T, Tran NGT, Ho V. Checkpoint Inhibitors and the Gut. J Clin Med 2022; 11:824. [PMID: 35160275 PMCID: PMC8836963 DOI: 10.3390/jcm11030824] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/27/2022] [Accepted: 02/01/2022] [Indexed: 12/18/2022] Open
Abstract
Checkpoint inhibitors have revolutionized treatments in modern oncology, including many conditions previously relegated to palliative therapies only. However, emerging recognition of checkpoint inhibitor-related adverse events has complicated the status of checkpoint inhibitor-related therapies. This review article discusses gastrointestinal adverse events as a result of checkpoint inhibitor therapy, as well as limitations of current guidelines, thus providing recommendations for guideline revision and future study direction.
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Affiliation(s)
- Tuan Tran
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (N.G.T.T.); (V.H.)
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Graziani G, Lisi L, Tentori L, Navarra P. Monoclonal Antibodies to CTLA-4 with Focus on Ipilimumab. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:295-350. [PMID: 35165868 DOI: 10.1007/978-3-030-91311-3_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) is a negative regulator of T-cell-mediated immune responses which plays a critical role in suppressing autoimmunity and maintaining immune homeostasis. Because of its inhibitory activity on T cells, CTLA-4 has been investigated as a drug target to induce immunostimulation, blocking the interaction with its ligands. The antitumor effects mediated by CTLA-4 blockade have been attributed to a sustained active immune response against cancer cells, due to the release of a brake on T cell activation. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human anti-CTLA-4 IgG1κ monoclonal antibody (mAb) that represents the first immune checkpoint inhibitor approved as monotherapy by FDA and EMA in 2011 for the treatment of unresectable/metastatic melanoma. In 2015, FDA also granted approval to ipilimumab monotherapy as adjuvant treatment of stage III melanoma to reduce the risk of tumour recurrence. The subsequent approved indications of ipilimumab for metastatic melanoma, regardless of BRAF mutational status, and other advanced/metastatic solid tumours always involve its use in association with the anti-programmed cell death protein 1 (PD-1) mAb nivolumab. Currently, ipilimumab is evaluated in ongoing clinical trials for refractory/advanced solid tumours mainly in combination with additional immunostimulating agents.
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Affiliation(s)
- Grazia Graziani
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Lucia Lisi
- Section of Pharmacology, Department of Healthcare Surveillance and Bioethics, Catholic University Medical School, Catholic University of the Sacred Heart, Rome, Italy
| | - Lucio Tentori
- Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Pierluigi Navarra
- Section of Pharmacology, Department of Healthcare Surveillance and Bioethics, Catholic University Medical School, Catholic University of the Sacred Heart, Rome, Italy
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43
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Lisi L, Lacal PM, Martire M, Navarra P, Graziani G. Clinical experience with CTLA-4 blockade for cancer immunotherapy: From the monospecific monoclonal antibody ipilimumab to probodies and bispecific molecules targeting the tumor microenvironment. Pharmacol Res 2021; 175:105997. [PMID: 34826600 DOI: 10.1016/j.phrs.2021.105997] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/09/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022]
Abstract
The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an inhibitory regulator of T-cell mediated responses that has been investigated as target of monoclonal antibodies (mAbs) for cancer immunotherapy. The anti-CTLA-4 mAb ipilimumab represents the first immune checkpoint inhibitor that significantly improved overall survival in patients with unresectable/metastatic melanoma. The subsequent approved indications (often in the first-line setting) for melanoma and other advanced/metastatic solid tumors always require ipilimumab combination with nivolumab, an anti-programmed cell death protein 1 (PD-1) mAb. However, the improved clinical efficacy of the mAb combination is associated with increased immune-related adverse events, which might require treatment discontinuation even in responding patients. This drawback is expected to be overcome by the recent development of anti-CTLA-4 probodies proteolitycally activated in the tumor microenvironment and bispecific molecules targeting both CTLA-4 and PD-1, whose co-expression is characteristic of tumor-infiltrating T cells. These molecules would preferentially stimulate immune responses against the tumor, reducing toxicity toward normal tissues.
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Affiliation(s)
- Lucia Lisi
- Section of Pharmacology, Department of Healthcare surveillance and Bioethics, Catholic University Medical School, Largo F. Vito 1, 00168 Rome, Italy.
| | | | - Maria Martire
- Section of Pharmacology, Department of Healthcare surveillance and Bioethics, Catholic University Medical School, Largo F. Vito 1, 00168 Rome, Italy.
| | - Pierluigi Navarra
- Section of Pharmacology, Department of Healthcare surveillance and Bioethics, Catholic University Medical School, Largo F. Vito 1, 00168 Rome, Italy.
| | - Grazia Graziani
- IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
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44
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Westdorp H, Sweep MWD, Gorris MAJ, Hoentjen F, Boers-Sonderen MJ, van der Post RS, van den Heuvel MM, Piet B, Boleij A, Bloemendal HJ, de Vries IJM. Mechanisms of Immune Checkpoint Inhibitor-Mediated Colitis. Front Immunol 2021; 12:768957. [PMID: 34777387 PMCID: PMC8586074 DOI: 10.3389/fimmu.2021.768957] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.
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Affiliation(s)
- Harm Westdorp
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
- Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Mark W. D. Sweep
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
- Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Mark A. J. Gorris
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
- Oncode Institute, Nijmegen, Netherlands
| | - Frank Hoentjen
- Department of Gastroenterology, Radboud University Medical Centre, Nijmegen, Netherlands
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | | | - Rachel S. van der Post
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
| | | | - Berber Piet
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
- Department of Pulmonary Diseases, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Annemarie Boleij
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Haiko J. Bloemendal
- Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, Netherlands
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45
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Liu Z, Liu X, Liang J, Liu Y, Hou X, Zhang M, Li Y, Jiang X. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects. Front Immunol 2021; 12:765101. [PMID: 34675942 PMCID: PMC8524467 DOI: 10.3389/fimmu.2021.765101] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.
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Affiliation(s)
- Zhuoyan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxin Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Meichuan Zhang
- R&D Department, Caleb BioMedical Technology Co. Ltd, Guangzhou, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Kobayashi T, Iwama S, Yasuda Y, Okada N, Okuji T, Ito M, Onoue T, Goto M, Sugiyama M, Tsunekawa T, Takagi H, Hagiwara D, Ito Y, Suga H, Banno R, Yokota K, Hase T, Morise M, Hashimoto N, Ando M, Fujimoto Y, Hibi H, Sone M, Ando Y, Akiyama M, Hasegawa Y, Arima H. Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study. J Immunother Cancer 2021; 8:jitc-2020-000779. [PMID: 32606047 PMCID: PMC7328763 DOI: 10.1136/jitc-2020-000779] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2020] [Indexed: 12/21/2022] Open
Abstract
Background Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM). Methods A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint. Results Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05). Conclusions In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone. Clinical trials registration UMIN000019024.
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Affiliation(s)
- Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Yasuda
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norio Okada
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takayuki Okuji
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masaaki Ito
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Onoue
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Motomitsu Goto
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mariko Sugiyama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Taku Tsunekawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Takagi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Hagiwara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Ito
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of CKD Initiatives Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidetaka Suga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryoichi Banno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan
| | - Kenji Yokota
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Morise
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naozumi Hashimoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Ando
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Yasushi Fujimoto
- Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michihiko Sone
- Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Masashi Akiyama
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Hasegawa
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
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47
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Combination chemotherapeutic and immune-therapeutic anticancer approach via anti-PD-L1 antibody conjugated albumin nanoparticles. Int J Pharm 2021; 605:120816. [PMID: 34161810 DOI: 10.1016/j.ijpharm.2021.120816] [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] [Received: 04/21/2021] [Revised: 05/28/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
Anticancer regimens have been substantially enriched through monoclonal antibodies targeting immune checkpoints, programmed cell death-1/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4. Inconsistent clinical efficacy after solo immunotherapy may be compensated by nanotechnology-driven combination therapy. We loaded human serum albumin (HSA) nanoparticles with paclitaxel (PTX) via nanoparticle albumin-bound technology and pooled them with anti-PD-L1 monoclonal antibody through a pH-sensitive linker for targeting and immune response activation. Our tests demonstrated satisfactory preparation of paclitaxel-loaded, PD-L1-targeted albumin nanoparticles (PD-L1/PTX@HSA). They had small particle size (~200 nm) and polydispersity index (~0.12) and successfully incorporated each constituent. Relative to normal physiological pH, the formulation exhibited higher drug-release profiles favoring cancer cell-targeted release at low pH. Modifying nanoparticles with programmed cell death-ligand 1 increased cancer cell internalization in vitro and tumor accumulation in vivo in comparison with non-PD-L1-modified nanoparticles. PD-L1/PTX@HSA constructed by nanoparticle albumin-bound technology displayed successful tumor inhibition efficacy both in vitro and in vivo. There was successful effector T-cell infiltration, immunosuppressive programmed cell death-ligand 1, and regulatory T-cell suppression because of cytotoxic T-lymphocyte antigen-4 synergy. Moreover, PD-L1/PTX@HSA had low organ toxicity. Hence, the anti-tumor immune responses of PD-L1/PTX@HSA combined with chemotherapy and cytotoxic T-lymphocyte antigen-4 is a potential anti-tumor strategy for improving quantitative and qualitative clinical efficacy.
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48
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Kobayashi T, Iwama S, Sugiyama D, Yasuda Y, Okuji T, Ito M, Ito S, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Ito Y, Suga H, Banno R, Nishikawa H, Arima H. Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors. J Immunother Cancer 2021; 9:jitc-2021-002493. [PMID: 34011534 PMCID: PMC8137231 DOI: 10.1136/jitc-2021-002493] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Pituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs). METHODS In this case-control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles. RESULTS Eleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls. CONCLUSIONS This study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively. TRIAL REGISTRATION NUMBER UMIN000019024.
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Affiliation(s)
- Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Daisuke Sugiyama
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yoshinori Yasuda
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takayuki Okuji
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Masaaki Ito
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Sachiko Ito
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Mariko Sugiyama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takeshi Onoue
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Hiroshi Takagi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Daisuke Hagiwara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yoshihiro Ito
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Hidetaka Suga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Ryoichi Banno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.,Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Aichi, Japan
| | - Hiroyoshi Nishikawa
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.,Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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49
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Yang Y, Li X, Ma Z, Wang C, Yang Q, Byrne-Steele M, Hong R, Min Q, Zhou G, Cheng Y, Qin G, Youngyunpipatkul JV, Wing JB, Sakaguchi S, Toonstra C, Wang LX, Vilches-Moure JG, Wang D, Snyder MP, Wang JY, Han J, Herzenberg LA. CTLA-4 expression by B-1a B cells is essential for immune tolerance. Nat Commun 2021; 12:525. [PMID: 33483505 PMCID: PMC7822855 DOI: 10.1038/s41467-020-20874-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 12/17/2020] [Indexed: 01/11/2023] Open
Abstract
CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.
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Affiliation(s)
- Yang Yang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
| | - Xiao Li
- The Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, USA
| | - Zhihai Ma
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | | | | | | | - Rongjian Hong
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Qing Min
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Gao Zhou
- The Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, USA
| | - Yong Cheng
- St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Guang Qin
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | | | - James B Wing
- Laboratory of Human Immunology (Single Cell Immunology), World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Laboratory of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Christian Toonstra
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA
| | - Lai-Xi Wang
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA
| | - Jose G Vilches-Moure
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Denong Wang
- Tumor Glycomics Laboratory, SRI International Biosciences Division, Menlo Park, CA, USA
| | - Michael P Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Ji-Yang Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China
- Department of Microbiology and Immunology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jian Han
- iRepertoire Inc, Huntsville, AL, USA
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | - Leonore A Herzenberg
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
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50
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Hara K, Yamasaki K, Tahara M, Kimuro R, Yamaguchi Y, Suzuki Y, Kawabata H, Kawanami T, Fujimoto N, Yatera K. Immune checkpoint inhibitors-induced eosinophilic pneumonia: A case report. Thorac Cancer 2021; 12:720-724. [PMID: 33476070 PMCID: PMC7919115 DOI: 10.1111/1759-7714.13848] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/02/2021] [Accepted: 01/02/2021] [Indexed: 01/15/2023] Open
Abstract
A 78‐year‐old male with renal cell carcinoma was treated with combined immunotherapy of nivolumab and ipilimumab. After four courses of the treatment, a chest computed tomography (CT) revealed newly formed ground‐glass opacities (GGOs) in both the lower lung lobes; drug‐induced pneumonia was speculated. Eosinophil counts were elevated in both peripheral blood and bronchoalveolar lavage fluid. Both the immune checkpoint inhibitors (ICIs) were discontinued, following which the chest CT findings improved. Based on these findings, a diagnosis of ICI‐induced eosinophilic pneumonia was made. Hence, clinicians should be wary of the risk of eosinophilic pneumonia during ICI‐anticancer therapy.
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Affiliation(s)
- Kanako Hara
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kei Yamasaki
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Masahiro Tahara
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Rieko Kimuro
- Department of Urology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yudai Yamaguchi
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yu Suzuki
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hiroki Kawabata
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Toshinori Kawanami
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Naohiro Fujimoto
- Department of Urology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kazuhiro Yatera
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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