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Mittal P, Battaglin F, Yang Y, Soni S, Stintzing S, Parikh AR, Ashouri K, Algaze S, Jayachandran P, Torres-Gonzalez L, Zhang W, Cremolini C, Heinemann V, Millstein J, Singh IK, Lenz HJ. Genetic Polymorphisms in MHC Classes I and II Predict Outcomes in Metastatic Colorectal Cancer. Int J Mol Sci 2025; 26:2556. [PMID: 40141198 PMCID: PMC11942614 DOI: 10.3390/ijms26062556] [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: 01/27/2025] [Revised: 03/07/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of the antigen presentation pathway. Therefore, the present study aimed to explore the effect of genetic variants in genes involved in MHC class I and II pathways in patients treated with first-line chemotherapy in combination with targeted antibodies in metastatic colorectal cancer (mCRC) patients. Genomic DNA from the blood samples of 775 patients enrolled in three independent, randomized, first-line trials, namely TRIBE (FOLFIRI-bevacizumab, N = 215), FIRE-3 (FOLFIRI-bevacizumab, N = 107; FOLFIRI-cetuximab, N = 129), and MAVERICC (FOLFIRI-bevacizumab, N = 163; FOLFOX6-bevacizumab, N = 161), was genotyped through OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on the outcome of 40 selected SNPs in 22 genes of MHC class I and II pathways was analyzed. We identified several SNPs in multiple genes associated with targeted treatment benefits across different treatment arms in our study population (p < 0.05). Treatment-SNP interaction analyses confirmed a significant treatment interaction with the targeted agents (bevacizumab vs. cetuximab) and the chemotherapy backbone (FOLFIRI vs. FOLFOX) in certain selected SNPs. Our results highlight a potential role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with differential effects based on the biologic agent and chemotherapy backbone. These biomarkers, when further validated, may contribute to personalized treatment strategies for mCRC patients.
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Affiliation(s)
- Pooja Mittal
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi 110019, India
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Yan Yang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Sebastian Stintzing
- Medical Department, Division of Oncology and Hematology, Charité Universitätsmedizin, 10117 Berlin, Germany
| | - Aparna R. Parikh
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Karam Ashouri
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Sandra Algaze
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Priya Jayachandran
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Lesly Torres-Gonzalez
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
| | - Chiara Cremolini
- Department of Medical Oncology, University of Pisa, 56126 Pisa, Italy
| | - Volker Heinemann
- Department of Hematology/Oncology, LMU Klinikum, University of Munich, Comprehensive Cancer Center Munich, 81377 Munich, Germany
| | - Joshua Millstein
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Indrakant K. Singh
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi 110019, India
- Delhi School of Public Health, Institute of Eminence, University of Delhi, New Delhi 110007, India
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (P.M.)
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Webb LM, Okuno SH, Ransom RC, Van Gompel JJ, Humes AL, Sarkaria JN, Ruff MW. Recurrent adamantinomatous craniopharyngioma stabilized with tocilizumab and bevacizumab: illustrative case. JOURNAL OF NEUROSURGERY. CASE LESSONS 2025; 9:CASE24410. [PMID: 39805108 PMCID: PMC11734617 DOI: 10.3171/case24410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/08/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Adamantinomatous craniopharyngiomas (ACPs) are slow-growing, cystic, highly morbid central nervous system tumors located adjacent to vital structures including the pituitary, hypothalamus, and optic chiasm. Tumor recurrence is common. Treatment relies on resection with or without adjuvant radiation and is highly individualized. Targeted chemotherapies have not been routinely used in the treatment of ACPs. OBSERVATIONS The authors present the case of an adult patient with recurrent ACP that was clinically and radiologically stabilized with a combination of bevacizumab and tocilizumab every 3 weeks. LESSONS The combination of tocilizumab and bevacizumab could be an effective therapy for shrinkage of the cystic and solid components of ACP, sparing patients from further neurological damage from the tumor, additional surgery, or radiation. The patient's positive response to tocilizumab and bevacizumab supports the growing literature that interleukin-6 and vascular endothelial growth factor are important for ACP pathogenesis. The patient's response supports prior research, suggesting that systemic chemotherapy can be effectively delivered to this rare brain tumor. https://thejns.org/doi/10.3171/CASE24410.
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Affiliation(s)
- Lauren M. Webb
- Department of Neurology, Mayo Clinic, Rochester, Minnesota;
| | - Scott H. Okuno
- Department of Oncology, Mayo Clinic, Rochester, Minnesota;
| | - Ryan C. Ransom
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota;
| | | | - Allison L. Humes
- Department of Oncology, Mayo Clinic Health System, Southwest Wisconsin, La Crosse, Wisconsin
| | - Jann N. Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Michael W. Ruff
- Department of Neurology, Mayo Clinic, Rochester, Minnesota;
- Department of Oncology, Mayo Clinic, Rochester, Minnesota;
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3
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Jiang Z, Fang Z, Hong D, Wang X. Cancer Immunotherapy with "Vascular-Immune" Crosstalk as Entry Point: Associated Mechanisms, Therapeutic Drugs and Nano-Delivery Systems. Int J Nanomedicine 2024; 19:7383-7398. [PMID: 39050878 PMCID: PMC11268745 DOI: 10.2147/ijn.s467222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/04/2024] [Indexed: 07/27/2024] Open
Abstract
Tumor vessels characterized by abnormal functions and structures hinder the infiltration and immune antigen presentation of immune cells by inducing the formation of an immunosuppressive microenvironment ("cold" environment). Vascular-targeted therapy has been proven to enhance immune stimulation and the effectiveness of immunotherapy by modulating the "cold" microenvironment, such as hypoxia and an acidic microenvironment. Notably, a therapeutic strategy based on "vascular-immune" crosstalk can achieve dual regulation of tumor vessels and the immune system by reprogramming the tumor microenvironment (TME), thus forming a positive feedback loop between tumor vessels and the immune microenvironment. From this perspective, we discuss the factors of tumor angiogenesis and "cold" TME formation. Building on this foundation, some vascular-targeted therapeutic drugs will be elaborated upon in detail to achieve dual regulation of tumor vessels and immunity. More importantly, we focus on cutting-edge nanotechnology in view of "vascular-immune" crosstalk and discuss the rational fabrication of tailor-made nanosystems for efficiently enhancing immunotherapy.
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Affiliation(s)
- Zhijie Jiang
- Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, People’s Republic of China
| | - Zhujun Fang
- Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, People’s Republic of China
| | - Dongsheng Hong
- Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, People’s Republic of China
| | - Xiaojuan Wang
- Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, People’s Republic of China
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Birnboim-Perach R, Benhar I. Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment. Int J Biol Sci 2024; 20:3911-3922. [PMID: 39113705 PMCID: PMC11302893 DOI: 10.7150/ijbs.93697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 06/29/2024] [Indexed: 08/10/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have heralded a new era in immunotherapy, representing a pivotal breakthrough in cancer treatment. Their impact is profound, with ICIs standing as some of the most prescribed anticancer therapies today. Notably, their ability to induce long-term remission even after treatment cessation provides genuine hope for achieving durable cures. However, despite these strides, challenges persist in the landscape of oncology, including resistance phenomena, immune-related adverse events, and suboptimal response rates. In response to these challenges, combination therapy emerges as a promising approach, poised to enhance treatment outcomes and address limitations inherent to single-agent ICI therapy. By synergistically targeting multiple pathways, combination therapy holds the potential to augment therapeutic efficacy while mitigating toxicity and impeding the emergence of resistance mechanisms. Understanding the intricacies underlying resistance development and adverse events is paramount in devising novel and refined combination strategies. A timeline showing FDA approvals of ICIs combination is shown in Figure 1. This review aims to provide a comprehensive and up-to-date examples of different combined therapy strategies that can be used to overcome various challenges regarding ICI treatment. Through the exploration of innovative therapeutic combinations, we aim to provide clinicians and researchers with actionable knowledge to optimize patient outcomes and propel the field of immuno-oncology forward.
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Affiliation(s)
- Racheli Birnboim-Perach
- Department of Molecular Microbiology and Biotechnology, The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel
| | - Itai Benhar
- Department of Molecular Microbiology and Biotechnology, The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel
- Cancer Biology Research Center, Tel Aviv University, Tel-Aviv 69978, Israel
- The Tel Aviv University Center for Combatting Pandemics, Tel-Aviv University, Tel-Aviv 69978, Israel
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Soberanis Pina P, Oza AM. Methodical Manipulation of the TME in Ovarian Cancer. Clin Cancer Res 2024; 30:12-16. [PMID: 37939000 DOI: 10.1158/1078-0432.ccr-23-2365] [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: 09/19/2023] [Revised: 10/16/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023]
Abstract
The complex interplay between ovarian cancer cells and the tumor microenvironment (TME) modulates progression, with dynamic cellular interactions influenced by external modulators, including neoadjuvant chemotherapy (NACT). A recent article described the alterations within the TME following NACT, either with or without bevacizumab, in ovarian cancer. See related article by Tavira et al., p. 176.
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Affiliation(s)
- Pamela Soberanis Pina
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Amit M Oza
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Matteucci L, Bittoni A, Gallo G, Ridolfi L, Passardi A. Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era? Cancers (Basel) 2023; 15:5189. [PMID: 37958363 PMCID: PMC10648369 DOI: 10.3390/cancers15215189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/21/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.
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Affiliation(s)
- Laura Matteucci
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Graziana Gallo
- Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, “Maurizio Bufalini” Hospital, 47521 Cesena, Italy
| | - Laura Ridolfi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
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Astore S, Baciarello G, Cerbone L, Calabrò F. Primary and acquired resistance to first-line therapy for clear cell renal cell carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:517-546. [PMID: 37842234 PMCID: PMC10571064 DOI: 10.20517/cdr.2023.33] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/26/2023] [Accepted: 07/11/2023] [Indexed: 10/17/2023]
Abstract
The introduction of first-line combinations had improved the outcomes for metastatic renal cell carcinoma (mRCC) compared to sunitinib. However, some patients either have inherent resistance or develop resistance as a result of the treatment. Depending on the kind of therapy employed, many factors underlie resistance to systemic therapy. Angiogenesis and the tumor immune microenvironment (TIME), nevertheless, are inextricably linked. Although angiogenesis and the manipulation of the tumor microenvironment are linked to hypoxia, which emerges as a hallmark of renal cell carcinoma (RCC) pathogenesis, it is only one of the potential elements involved in the distinctive intra- and inter-tumor heterogeneity of RCC that is still dynamic. We may be able to more correctly predict therapy response and comprehend the mechanisms underlying primary or acquired resistance by integrating tumor genetic and immunological markers. In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients' treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.
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Affiliation(s)
- Serena Astore
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
| | | | - Linda Cerbone
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
| | - Fabio Calabrò
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
- Medical Oncology, IRCSS, National Cancer Institute Regina Elena, Rome 00128, Italy
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8
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Park JA, Espinosa-Cotton M, Guo HF, Monette S, Cheung NKV. Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody. J Immunother Cancer 2023; 11:jitc-2023-006680. [PMID: 36990507 PMCID: PMC10069597 DOI: 10.1136/jitc-2023-006680] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Success of T cell immunotherapy hinges on the tumor microenvironment (TME), and abnormal tumor vasculature is a hallmark of most solid tumors and associated with immune evasion. The efficacy of T cell engaging bispecific antibody (BsAb) treatment relies on the successful trafficking and cytolytic activity of T cells in solid tumors. Normalization of tumor vasculature using vascular endothelial growth factor (VEGF) blockades could improve efficacy of BsAb-based T cell immunotherapy. METHODS Anti-human VEGF (bevacizumab, BVZ) or anti-mouse VEGFR2 antibody (DC101) was used as VEGF blockade, and ex vivo armed T cells (EATs) carrying anti-GD2, anti-HER2, or anti-glypican3 (GPC3) IgG-(L)-scFv platformed BsAb were used. BsAb-driven intratumoral T cell infiltration and in vivo antitumor response were evaluated using cancer cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) carried out in BALB-Rag2 -/-IL-2R-γc-KO (BRG) mice. VEGF expression on human cancer cell lines was analyzed by flow cytometry, and VEGF levels in mouse serum were measured using VEGF Quantikine ELISA Kit. Tumor infiltrating lymphocytes (TILs) were evaluated using flow cytometry and by bioluminescence; both TILs and tumor vasculature were studied using immunohistochemistry. RESULTS VEGF expression on cancer cell lines increased with seeding density in vitro. BVZ significantly reduced serum VEGF levels in mice. BVZ or DC101 increased high endothelial venules (HEVs) in the TME and substantially enhanced (2.1-8.1 fold) BsAb-driven T cell infiltration into neuroblastoma and osteosarcoma xenografts, which was preferential for CD8(+) TILs versus CD4(+) TILs, leading to superior antitumor effects in multiple CDX and PDX tumor models without added toxicities. CONCLUSIONS VEGF blockade using specific antibodies against VEGF or VEGFR2 increased HEVs in the TME and cytotoxic CD8(+) TILs, significantly improving the therapeutic efficacy of EAT strategies in preclinical models, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies.
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Affiliation(s)
- Jeong A Park
- Pediatrics, Inha University Hospital, Incheon, Korea (the Republic of)
- Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | | | - Hong-Fen Guo
- Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Sebastien Monette
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Medicine, New York, New York, USA
| | - Nai-Kong V Cheung
- Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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9
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San-Román-Gil M, Torres-Jiménez J, Pozas J, Esteban-Villarrubia J, Albarrán-Fernández V, Álvarez-Ballesteros P, Chamorro-Pérez J, Rosero-Rodríguez D, Orejana-Martín I, Martínez-Delfrade Í, Reguera-Puertas P, Fuentes-Mateos R, Ferreiro-Monteagudo R. Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma. Cancers (Basel) 2023; 15:863. [PMID: 36765821 PMCID: PMC9913409 DOI: 10.3390/cancers15030863] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
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Affiliation(s)
- María San-Román-Gil
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | - Javier Torres-Jiménez
- Medical Oncology Department, Clínico San Carlos University Hospital, 28040 Madrid, Spain
| | - Javier Pozas
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
| | | | | | | | - Jesús Chamorro-Pérez
- Medical Oncology Department, Ramón y Cajal University Hospital, 28034 Madrid, Spain
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10
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Bu MT, Chandrasekhar P, Ding L, Hugo W. The roles of TGF-β and VEGF pathways in the suppression of antitumor immunity in melanoma and other solid tumors. Pharmacol Ther 2022; 240:108211. [PMID: 35577211 PMCID: PMC10956517 DOI: 10.1016/j.pharmthera.2022.108211] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 12/13/2022]
Abstract
Immune checkpoint blockade (ICB) has become well-known in cancer therapy, strengthening the body's antitumor immune response rather than directly targeting cancer cells. Therapies targeting immune inhibitory checkpoints, such as PD-1, PD-L1, and CTLA-4, have resulted in impressive clinical responses across different types of solid tumors. However, as with other types of cancer treatments, ICB-based immunotherapy is hampered by both innate and acquired drug resistance. We previously reported the enrichment of gene signatures associated with wound healing, epithelial-to-mesenchymal, and angiogenesis processes in the tumors of patients with innate resistance to PD-1 checkpoint antibody therapy; we termed these the Innate Anti-PD-1 Resistance Signatures (IPRES). The TGF-β and VEGFA pathways emerge as the dominant drivers of IPRES-associated processes. Here, we review these pathways' functions, their roles in immunosuppression, and the currently available therapies that target them. We also discuss recent developments in the targeting of TGF-β using a specific antibody class termed trap antibody. The application of trap antibodies opens the promise of localized targeting of the TGF-β and VEGFA pathways within the tumor microenvironment. Such specificity may offer an enhanced therapeutic window that enables suppression of the IPRES processes in the tumor microenvironment while sparing the normal homeostatic functions of TGF-β and VEGFA in healthy tissues.
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Affiliation(s)
- Melissa T Bu
- Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Pallavi Chandrasekhar
- Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Lizhong Ding
- Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy UCLA, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Willy Hugo
- Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy UCLA, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
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Translational landscape of glioblastoma immunotherapy for physicians: guiding clinical practice with basic scientific evidence. J Hematol Oncol 2022; 15:80. [PMID: 35690784 PMCID: PMC9188021 DOI: 10.1186/s13045-022-01298-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023] Open
Abstract
Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease—switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy—which utilizes strategies to reenergize or alter the immune system to target cancer—have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.
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PD-L1: Can it be a biomarker for the prognosis or a promising therapeutic target in cervical cancer? Int Immunopharmacol 2021; 103:108484. [PMID: 34954558 DOI: 10.1016/j.intimp.2021.108484] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/12/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022]
Abstract
Cervical cancer is one of the most common in the female genital tract and remains a leading cause that threatens the health and lives of women worldwide, although preventive vaccines and early diagnosis have reduced mortality. While treatment by operation and chemoradiotherapy for early-stage patients achieve good outcomes, the great majority of cervical cancers caused by the human papilloma virus (HPV) make immunotherapy realizable for patients with advanced and recurrent cervical cancer. To date, some clinical trials of checkpoint immunotherapy in cervical cancer have indicated significant benefits of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors, providing strong evidence for PD-1/PD-L1 as a therapeutic target. In this review article, we discuss the role of PD-L1 and the application of PD-L1 inhibitors in cervical cancer, with the aim of providing direction for future research.
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Manyam M, Stephens AJ, Kennard JA, LeBlanc J, Ahmad S, Kendrick JE, Holloway RW. A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer. Gynecol Oncol 2021; 163:481-489. [PMID: 34686353 DOI: 10.1016/j.ygyno.2021.10.069] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/01/2021] [Accepted: 10/10/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Our objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). METHODS Olvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. RESULTS Twelve patients (median age: 69 years, range: 45-77) with median 5 prior therapies (range: 2-10) and 2 prior platinum lines (range: 1-5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7-34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. CONCLUSIONS Oncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.
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Affiliation(s)
- Madhavi Manyam
- Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL 32804, USA
| | - Amanda J Stephens
- Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL 32804, USA
| | - Jessica A Kennard
- Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL 32804, USA
| | - Jane LeBlanc
- Office of Clinical Research, AdventHealth Cancer Institute, Orlando, FL 32804, USA
| | - Sarfraz Ahmad
- Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL 32804, USA.
| | - James E Kendrick
- Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL 32804, USA
| | - Robert W Holloway
- Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL 32804, USA.
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Singh A, Beechinor RJ, Huynh JC, Li D, Dayyani F, Valerin JB, Hendifar A, Gong J, Cho M. Immunotherapy Updates in Advanced Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13092164. [PMID: 33946408 PMCID: PMC8125389 DOI: 10.3390/cancers13092164] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Advanced hepatocellular carcinoma (HCC) carries a grim prognosis, which has historically been compounded by a lack of available systemic therapies. Sorafenib monotherapy was the standard of care for front-line treatment of advanced HCC for many years, despite both poor tolerability and lack of durable responses. In the past few years, there have been several clinical trials evaluating the efficacy of immune checkpoint inhibitors for advanced HCC. Use of immune checkpoint inhibitors alone, and in combination with targeted therapies, has led to improved outcomes in both treatment-naïve and subsequent line treatment of advanced HCC. Here we review the role of immunotherapy in the treatment of HCC, describe the mechanistic basis for combination with targeted therapy, and summarize the recent published data as well as ongoing clinical trials for the use of immunotherapy in the treatment of advanced HCC. Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment.
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Affiliation(s)
- Amisha Singh
- Internal Medicine, University of California, Davis, Sacramento, CA 95817, USA;
| | | | - Jasmine C. Huynh
- Hematology Oncology, University of California, Davis, Sacramento, CA 95817, USA;
| | - Daneng Li
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA 91010, USA;
| | - Farshid Dayyani
- Hematology Oncology, University of California, Irvine, Irvine, CA 92868, USA; (F.D.); (J.B.V.)
| | - Jennifer B. Valerin
- Hematology Oncology, University of California, Irvine, Irvine, CA 92868, USA; (F.D.); (J.B.V.)
| | - Andrew Hendifar
- Hematology Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.H.); (J.G.)
| | - Jun Gong
- Hematology Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.H.); (J.G.)
| | - May Cho
- Hematology Oncology, University of California, Irvine, Irvine, CA 92868, USA; (F.D.); (J.B.V.)
- Correspondence:
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Yang Q, Shen R, Xu H, Shi X, Xu L, Zhang L, Fan X, Jin X. Comprehensive analyses of PBRM1 in multiple cancer types and its association with clinical response to immunotherapy and immune infiltrates. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:465. [PMID: 33850862 PMCID: PMC8039713 DOI: 10.21037/atm-21-289] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background The prognostic value of polybromo 1 (PBRM1) gene mutations in clear cell renal carcinoma (CCRCC) with anti-programmed death-ligand 1 (PD-L1) therapy remains controversial, and few studies have reported the impact of PBRM1 mutations in other cancer types. Methods The patient information was obtained from cBioPortal and the Tumor Immune Estimation Resource (TIMER) databases. Mann-Whitney U test were used for correlation analysis. For survival analyses, Kaplan-Meier survival curves were used and compared using the log-rank test. Cox’s regression model was used to perform univariable and multivariable analyses Results Our study, for the first time, performed comprehensive analyses of PBRM1 mutation frequency, PBRM1 expression, relationship of PBRM1 mutations with clinical benefit from immunotherapy, and PBRM1 expression with immune infiltrates in diverse cancer types. The results showed that the expression of PBRM1 was significantly lower in diverse cancer types compared with normal tissues. Based on multivariable analysis, PBRM1 mutations trended towards worse clinical outcomes from anti-PD-L1 in CCRCC, lung adenocarcinoma (LUAD), bladder urothelial carcinoma (BLCA), and skin cutaneous melanoma (SKCM), and a significant association was observed in LUAD and BLCA. PBRM1 mutations were associated with higher TMB in diverse cancer types and significant associations were observed in LUAD and BLCA. The expression of PBRM1 was found to positively correlate with immune infiltrates in diverse cancer types. Conclusions Our findings suggested caution in starting immunotherapy alone in PBRM1 mutant patients. Further studies are needed to improve treatment for PBRM1 mutant patients.
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Affiliation(s)
- Qiuan Yang
- Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Rong Shen
- Department of Chemotherapy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hanlin Xu
- Thoracic Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | | | | | | | - Xinglong Fan
- Thoracic Department, Qilu Hospital of Shandong University (Qingdao), Qingdao, China
| | - Xiangfeng Jin
- Thoracic Surgery Department, The Affiliated Hospital of Qingdao University, Qingdao, China
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Stühler V, Rausch S, Maas JM, Stenzl A, Bedke J. Combination of immune checkpoint inhibitors and tyrosine kinase inhibitors for the treatment of renal cell carcinoma. Expert Opin Biol Ther 2021; 21:1215-1226. [PMID: 33576709 DOI: 10.1080/14712598.2021.1890713] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION We have experienced several paradigm shifts and substantial changes in the treatment of metastatic renal cell carcinoma (mRCC) over the last two decades. Combination therapy with immune checkpoint inhibitors (ICI) as a dual combination (ICI-ICI) or with VEGFR-tyrosine kinase inhibitors (VEGF-TKI) has shown remarkable efficacy in mRCC patients and has become the standard of care in first-line therapy. AREAS COVERED In this review, we will discuss the background as well as the benefits of combining ICI with TKI compared to ICI-ICI combination therapy for mRCC treatment and will also briefly highlight biomarkers for patient selection on therapies to improve patient outcomes and limit toxicities. EXPERT OPINION Due to the mediated additional anti-tumor effects, there is a strong rationale to combine ICIs and TKIs for mRCC therapy. When comparing first-line therapy options, the exceptionally higher ORR and PFS for the ICI-TKI combinations should be highlighted, whereas, nevertheless, the complete response rate is slightly higher for the ICI-ICI combination. In terms of an individualized therapeutic approach, biomarkers predicting the success or failure of an anti-VEGF-based regimen or ICI therapy as a corresponding mono - or combination therapy are lacking so far, however, gene expression signatures can be a landmark in this field.
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Affiliation(s)
- Viktoria Stühler
- Department of Urology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Steffen Rausch
- Department of Urology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Jan Moritz Maas
- Department of Urology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Jens Bedke
- Department of Urology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany
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Wiwatchaitawee K, Quarterman JC, Geary SM, Salem AK. Enhancement of Therapies for Glioblastoma (GBM) Using Nanoparticle-based Delivery Systems. AAPS PharmSciTech 2021; 22:71. [PMID: 33575970 DOI: 10.1208/s12249-021-01928-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/10/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Current FDA-approved treatments include surgical resection, radiation, and chemotherapy, while hyperthermia, immunotherapy, and most relevantly, nanoparticle (NP)-mediated delivery systems or combinations thereof have shown promise in preclinical studies. Drug-carrying NPs are a promising approach to brain delivery as a result of their potential to facilitate the crossing of the blood-brain barrier (BBB) via two main types of transcytosis mechanisms: adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). Their ability to accumulate in the brain can thus provide local sustained release of tumoricidal drugs at or near the site of GBM tumors. NP-based drug delivery has the potential to significantly reduce drug-related toxicity, increase specificity, and consequently improve the lifespan and quality of life of patients with GBM. Due to significant advances in the understanding of the molecular etiology and pathology of GBM, the efficacy of drugs loaded into vectors targeting this disease has increased in both preclinical and clinical settings. Multitargeting NPs, such as those incorporating multiple specific targeting ligands, are an innovative technology that can lead to decreased off-target effects while simultaneously having increased accumulation and action specifically at the tumor site. Targeting ligands can include antibodies, or fragments thereof, and peptides or small molecules, which can result in a more controlled drug delivery system compared to conventional drug treatments. This review focuses on GBM treatment strategies, summarizing current options and providing a detailed account of preclinical findings with prospective NP-based approaches aimed at improving tumor targeting and enhancing therapeutic outcomes for GBM patients.
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Stühler V, Rausch S, Stenzl A, Bedke J. Genetic analysis of primary renal cell carcinoma to determine treatment approaches. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021. [DOI: 10.1080/23808993.2021.1874822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Viktoria Stühler
- Department of Urology, University Hospital Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - Steffen Rausch
- Department of Urology, University Hospital Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
| | - Jens Bedke
- Department of Urology, University Hospital Tuebingen, Eberhard-Karls-University Tuebingen, Tuebingen, Germany
- German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany
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Morganti S, Curigliano G. Combinations using checkpoint blockade to overcome resistance. Ecancermedicalscience 2020; 14:1148. [PMID: 33574893 PMCID: PMC7864692 DOI: 10.3332/ecancer.2020.1148] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Indexed: 12/11/2022] Open
Abstract
The advent of immunotherapy for cancer represented a paradigm shift in the treatment approach of neoplasia. Immune-checkpoint inhibitors (ICIs) were demonstrated to significantly improve outcomes, including overall survival across several cancer types, with yearly-durable responses. Nevertheless, many patients derive minor or no benefit with immune checkpoint (IC)-blockade, including patients with cancer types traditionally considered immunogenic. Combination strategies of ICIs with chemotherapy, radiotherapy, targeted therapies or other immunotherapy compounds have been conceived in order to boost the immune-responses and potentially overcome resistance to ICIs. This review focuses on mechanisms underlying resistance to IC-blockade and provides an overview of potential advantages and limitations of combination strategies currently under investigation.
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Affiliation(s)
- Stefania Morganti
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology (IEO), IRCCS, Via Ripamonti n.435, 20141, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono n. 7, 20122 Milan, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology (IEO), IRCCS, Via Ripamonti n.435, 20141, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono n. 7, 20122 Milan, Italy
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Plotnikov A, Kozer N, Cohen G, Carvalho S, Duberstein S, Almog O, Solmesky LJ, Shurrush KA, Babaev I, Benjamin S, Gilad S, Kupervaser M, Levin Y, Gershovits M, Ben-Avraham D, Barr HM. PRMT1 inhibition induces differentiation of colon cancer cells. Sci Rep 2020; 10:20030. [PMID: 33208761 PMCID: PMC7676271 DOI: 10.1038/s41598-020-77028-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022] Open
Abstract
Differentiation therapy has been recently revisited as a prospective approach in cancer therapy by targeting the aberrant growth, and repairing the differentiation and cell death programs of cancer cells. However, differentiation therapy of solid tumors is a challenging issue and progress in this field is limited. We performed High Throughput Screening (HTS) using a novel dual multiplex assay to discover compounds, which induce differentiation of human colon cancer cells. Here we show that the protein arginine methyl transferase (PRMT) type 1 inhibitor, MS023, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Differentiation changes in the highly aggressive human colon cancer cell line (HT-29) were proved by proteomic and genomic approaches. Growth of HT-29 xenograft in nude mice was significantly delayed upon MS023 treatment and immunohistochemistry of tumor indicated differentiation changes. These findings may lead to development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation.
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Affiliation(s)
- Alexander Plotnikov
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
| | - Noga Kozer
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Galit Cohen
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Silvia Carvalho
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Shirly Duberstein
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Ofir Almog
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Leonardo Javier Solmesky
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Khriesto A Shurrush
- Wohl Institute for Drug Discovery, Medicinal Chemistry Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Ilana Babaev
- Wohl Institute for Drug Discovery, Medicinal Chemistry Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Sima Benjamin
- Crown Institute for Genomics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Shlomit Gilad
- Crown Institute for Genomics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Meital Kupervaser
- de Botton Institute for Proteomics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Yishai Levin
- de Botton Institute for Proteomics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Michael Gershovits
- Mantoux Institute for Bioinformatics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Danny Ben-Avraham
- Mantoux Institute for Bioinformatics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Haim Michael Barr
- Wohl Institute for Drug Discovery, High Throughput Screening Unit, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
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Youssef G, Dietrich J. Ipilimumab: an investigational immunotherapy for glioblastoma. Expert Opin Investig Drugs 2020; 29:1187-1193. [PMID: 32945231 DOI: 10.1080/13543784.2020.1826436] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Glioblastoma (GBM) is the most common primary malignant central nervous system tumor and has a poor overall outcome despite an aggressive standard-of-care treatment. Hence, better therapeutic modalities are necessary. Immunotherapy is a novel modality that has an indirect action against the tumor cells through activation of an anti-tumor immune response. AREAS COVERED Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) belongs to a class of molecules called immune checkpoints that are inherently expressed on immune cells and lead to attenuation of the immune response. Inhibition of such molecules has been approved for the treatment of melanoma, and prolonged survival and complete responses have been reported in preclinical GBM mouse models. Ipilimumab inhibits CTLA-4 and is being investigated for the treatment of GBM, alone or in combination with other treatment modalities, in various preclinical and clinical studies, the results of the most relevant of which are discussed in this review. EXPERT OPINION Combining ipilimumab with other immunotherapy modalities and using it in specific conditions may increase the rate of objective responses in patients with GBM.
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Affiliation(s)
- Gilbert Youssef
- MGH Cancer Center, Massachusetts General Hospital & Harvard Medical School , Boston, MA, USA.,Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital & Harvard Medical School , Boston, MA, USA
| | - Jorg Dietrich
- MGH Cancer Center, Massachusetts General Hospital & Harvard Medical School , Boston, MA, USA.,Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital & Harvard Medical School , Boston, MA, USA
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22
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Kennedy SA, Morrissey ME, Dunne MR, O'Connell F, Butler CT, Cathcart MC, Buckley AM, Mehigan BJ, Larkin JO, McCormick P, Kennedy BN, O'Sullivan J. Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors. BMC Cancer 2020; 20:952. [PMID: 33008336 PMCID: PMC7532092 DOI: 10.1186/s12885-020-07430-y] [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: 05/18/2020] [Accepted: 09/16/2020] [Indexed: 11/17/2022] Open
Abstract
Background Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication. Method Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry. Results Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers. Conclusion Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.
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Affiliation(s)
- Susan A Kennedy
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland
| | - Maria E Morrissey
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland
| | - Fiona O'Connell
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland
| | - Clare T Butler
- UCD Conway Institute & UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland
| | - Mary-Clare Cathcart
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland
| | - Amy M Buckley
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland
| | | | | | | | - Breandán N Kennedy
- UCD Conway Institute & UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland
| | - Jacintha O'Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.
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Friedman CF, Snyder Charen A, Zhou Q, Carducci MA, Buckley De Meritens A, Corr BR, Fu S, Hollmann TJ, Iasonos A, Konner JA, Konstantinopoulos PA, Modesitt SC, Sharon E, Aghajanian C, Zamarin D. Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer. J Immunother Cancer 2020; 8:jitc-2020-001126. [PMID: 33004542 PMCID: PMC7534695 DOI: 10.1136/jitc-2020-001126] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2020] [Indexed: 12/14/2022] Open
Abstract
Background There are limited treatment options for patients with metastatic or recurrent cervical cancer. Platinum-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab remains the mainstay of advanced treatment. Pembrolizumab is Food and Drug Agency approved for programmed death ligand 1 (PD-L1) positive cervical cancer with a modest response rate. This is the first study to report the efficacy and safety of the PD-L1 antibody atezolizumab in combination with bevacizumab in advanced cervical cancer. Methods We report the results from a phase II, open-label, multicenter study (NCT02921269). Patients with advanced cervical cancer were treated with bevacizumab 15 mg/kg intravenous every 3 weeks and atezolizumab 1200 mg intravenous every 3 weeks. The primary objective was to measure the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results In the total evaluable population (n=10), zero patients achieved an objective response as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1, resulting in a confirmed ORR of 0%. Of note, there were two patients who achieved an unconfirmed PR. The DCR by RECIST V.1.1 was 60% (0% complete response, 0% partial response, 60% stable disease). Median PFS was 2.9 months (95% CI, 1.8 to 6) and median OS was 8.9 months (95% CI, 3.4 to 21.9). Safety results were generally consistent with the known safety profile of both drugs, notably with two high-grade neurologic events. Conclusions The combination of bevacizumab and atezolizumab did not meet the predefined efficacy endpoint, as addition of bevacizumab to PD-L1 blockade did not appear to enhance the ORR in cervical cancer.
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Affiliation(s)
- Claire F Friedman
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Alexandra Snyder Charen
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Qin Zhou
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Michael A Carducci
- Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | | | - Bradley R Corr
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Siqing Fu
- University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Travis J Hollmann
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Alexia Iasonos
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jason A Konner
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | | | - Susan C Modesitt
- University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Elad Sharon
- National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Maryland, USA
| | - Carol Aghajanian
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dmitriy Zamarin
- Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Chakravarty D, Huang L, Kahn M, Tewari AK. Immunotherapy for Metastatic Prostate Cancer: Current and Emerging Treatment Options. Urol Clin North Am 2020; 47:487-510. [PMID: 33008499 DOI: 10.1016/j.ucl.2020.07.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.
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Affiliation(s)
- Dimple Chakravarty
- Department of Urology and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Li Huang
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Matthew Kahn
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ashutosh K Tewari
- Department of Urology and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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25
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Marmorino F, Boccaccino A, Germani MM, Falcone A, Cremolini C. Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge. Cancers (Basel) 2020; 12:E2317. [PMID: 32824490 PMCID: PMC7465130 DOI: 10.3390/cancers12082317] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Abstract
The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of "immune-competent" TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.
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Affiliation(s)
- Federica Marmorino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Alessandra Boccaccino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Marco Maria Germani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Alfredo Falcone
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Risorgimento 36, 56126 Pisa, Italy; (F.M.); (A.B.); (M.M.G.); (A.F.)
- Unit of Medical Oncology, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
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26
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von der Lippe Gythfeldt H, Lien T, Tekpli X, Silwal-Pandit L, Borgen E, Garred Ø, Skjerven H, Schlichting E, Lundgren S, Wist E, Naume B, Kristensen V, Børresen-Dale AL, Lingjaerde OC, Engebraaten O. Immune phenotype of tumor microenvironment predicts response to bevacizumab in neoadjuvant treatment of ER-positive breast cancer. Int J Cancer 2020; 147:2515-2525. [PMID: 32488909 DOI: 10.1002/ijc.33108] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 04/02/2020] [Accepted: 04/30/2020] [Indexed: 12/24/2022]
Abstract
Antiangiogenic drugs are potentially a useful supplement to neoadjuvant chemotherapy for a subgroup of patients with human epidermal growth factor receptor 2 (HER2) negative breast cancer, but reliable biomarkers for improved response are lacking. Here, we report on a randomized phase II clinical trial to study the added effect of bevacizumab in neoadjuvant chemotherapy with FEC100 (5-fluorouracil, epirubicin and cyclophosphamide) and taxanes (n = 132 patients). Gene expression from the tumors was obtained before neoadjuvant treatment, and treatment response was evaluated by residual cancer burden (RCB) at time of surgery. Bevacizumab increased the proportion of complete responders (RCB class 0) from 5% to 20% among patients with estrogen receptor (ER) positive tumors (P = .02). Treatment with bevacizumab was associated with improved 8-year disease-free survival (P = .03) among the good responders (RCB class 0 or I). Patients treated with paclitaxel (n = 45) responded better than those treated with docetaxel (n = 21; P = .03). Improved treatment response was associated with higher proliferation rate and an immune phenotype characterized by high presence of classically activated M1 macrophages, activated NK cells and memory activated CD4 T cells. Treatment with bevacizumab increased the number of adverse events, including hemorrhage, hypertension, infection and febrile neutropenia, but despite this, the ECOG status was not affected.
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Affiliation(s)
- Hedda von der Lippe Gythfeldt
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Tonje Lien
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Xavier Tekpli
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Laxmi Silwal-Pandit
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Elin Borgen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Øystein Garred
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Helle Skjerven
- Department of Breast and Endocrine Surgery, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
| | - Ellen Schlichting
- Department of Breast and Endocrine Surgery, Oslo University Hospital, Oslo, Norway
| | - Steinar Lundgren
- Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Erik Wist
- Department of Oncology, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Bjørn Naume
- Department of Oncology, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Vessela Kristensen
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Anne-Lise Børresen-Dale
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole Christian Lingjaerde
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Informatics, University of Oslo, Oslo, Norway.,KG Jebsen Centre for B-Cell Malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Olav Engebraaten
- Department of Oncology, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
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27
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Talla SB, Rempel E, Endris V, Jenzer M, Allgäuer M, Schwab C, Kazdal D, Stögbauer F, Volckmar AL, Kocsmar I, Neumann O, Schirmacher P, Zschäbitz S, Duensing S, Budczies J, Stenzinger A, Kirchner M. Immuno-oncology gene expression profiling of formalin-fixed and paraffin-embedded clear cell renal cell carcinoma: Performance comparison of the NanoString nCounter technology with targeted RNA sequencing. Genes Chromosomes Cancer 2020; 59:406-416. [PMID: 32212351 DOI: 10.1002/gcc.22843] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 01/05/2023] Open
Abstract
Inflammatory gene signatures are currently being explored as predictive biomarkers for immune checkpoint blockade, and particularly for the treatment of renal cell cancers. From a diagnostic point of view, the nCounter analysis platform and targeted RNA sequencing are emerging alternatives to microarrays and comprehensive transcriptome sequencing in assessing formalin-fixed and paraffin-embedded (FFPE) cancer samples. So far, no systematic study has analyzed and compared the technical performance metrics of these two approaches. Filling this gap, we performed a head-to-head comparison of two commercially available immune gene expression assays, using clear cell renal cell cancer FFPE specimens. We compared the nCounter system that utilizes a direct hybridization technology without amplification with an NGS assay that is based on targeted RNA-sequencing with preamplification. We found that both platforms displayed high technical reproducibility and accuracy (Pearson coefficient: ≥0.96, concordance correlation coefficient [CCC]: ≥0.93). A density plot for normalized expression of shared genes on both platforms showed a comparable bi-modal distribution and dynamic range. RNA-Seq demonstrated relatively larger signaling intensity whereas the nCounter system displayed higher inter-sample variability. Estimated fold changes for all shared genes showed high correlation (Spearman coefficient: 0.73). This agreement is even better when only significantly differentially expressed genes were compared. Composite gene expression profiles, such as an interferon gamma (IFNg) signature, can be reliably inferred by both assays. In summary, our study demonstrates that focused transcript read-outs can reliably be achieved by both technologies and that both approaches achieve comparable results despite their intrinsic technical differences.
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Affiliation(s)
- Suranand B Talla
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Eugen Rempel
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany
| | - Volker Endris
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Maximilian Jenzer
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
| | - Michael Allgäuer
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Constantin Schwab
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Daniel Kazdal
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Fabian Stögbauer
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Anna-Lena Volckmar
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Ildiko Kocsmar
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Olaf Neumann
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany
| | - Stefanie Zschäbitz
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
| | - Stefan Duensing
- Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan Budczies
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany
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28
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Lafon M, Domblides C, Daste A, Sionneau B, Ravaud A, Bernhard JC, Gross-Goupil M. Atezolizumab for the treatment of renal cell carcinoma. Expert Opin Biol Ther 2020; 20:679-686. [PMID: 32245328 DOI: 10.1080/14712598.2020.1751113] [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: 10/24/2022]
Abstract
INTRODUCTION The therapeutic landscape of renal cell cancer has evolved rapidly over the past 2 years with nivolumab and ipilimumab for patients with metastatic disease and an intermediate or poor prognosis, in the first line setting. More recently, data from trials combining antiangiogenic agents and immune checkpoint inhibitors demonstrated a major benefit of this treatment approach for all patients. AREAS COVERED One of three recent trials evaluated the combination of atezolizumab, an anti-programmed death ligand 1 antibody, with bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody. In this manuscript, we summarize the preclinical, clinical, and safety data on atezolizumab for treatment of renal cell carcinoma and describe ongoing trials. EXPERT OPINION Atezolizumab was evaluated in combination with an antiangiogenic agent. These trials were designed based on the hypothesis that selecting patients according to the expression of programmed death ligand 1 would increase the benefit of the treatment combination. Despite positive effects on the primary endpoints progression-free survival and response rate in this selected population, overall survival in the global population did not meet the criteria for significance at the time of the intermediate analysis. The major information was a proposed tumor gene expression signature. The signature was predictive of the sensitivity to anti-angiogenic and/or immune checkpoint inhibitor therapy.
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Affiliation(s)
- Mathilde Lafon
- Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France
| | - Charlotte Domblides
- Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France.,Bordeaux University , Bordeaux, France
| | - Amaury Daste
- Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France
| | - Baptiste Sionneau
- Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France.,Bordeaux University , Bordeaux, France
| | - Alain Ravaud
- Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France.,Bordeaux University , Bordeaux, France
| | - Jean-Christophe Bernhard
- Bordeaux University , Bordeaux, France.,Department of Urology, Bordeaux University Hospital , Bordeaux, France
| | - Marine Gross-Goupil
- Department of Medical Oncology, Bordeaux University Hospital , Bordeaux, France
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29
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Reardon DA, Desjardins A, Vredenburgh JJ, O'Rourke DM, Tran DD, Fink KL, Nabors LB, Li G, Bota DA, Lukas RV, Ashby LS, Duic JP, Mrugala MM, Cruickshank S, Vitale L, He Y, Green JA, Yellin MJ, Turner CD, Keler T, Davis TA, Sampson JH. Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial. Clin Cancer Res 2020; 26:1586-1594. [DOI: 10.1158/1078-0432.ccr-18-1140] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 08/21/2019] [Accepted: 11/27/2019] [Indexed: 11/16/2022]
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30
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Xu W, Atkins MB, McDermott DF. Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol 2020; 17:137-150. [PMID: 32020040 DOI: 10.1038/s41585-020-0282-3] [Citation(s) in RCA: 179] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2020] [Indexed: 02/08/2023]
Abstract
Kidney cancer has unique features that make this malignancy attractive for therapeutic approaches that target components of the immune system. Immune checkpoint inhibition is a well-established part of kidney cancer treatment, and rapid advances continue to be made in this field. Initial preclinical studies that elucidated the biology of the programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) immune checkpoints led to a series of clinical trials that resulted in regulatory approval of nivolumab and the combination of ipilimumab plus nivolumab for the treatment of advanced renal cell carcinoma. Subsequent data led to approvals of combination strategies of immune checkpoint inhibition plus agents that target the vascular endothelial growth factor receptor and a shift in the current standard of renal cell carcinoma care. However, controversies remain regarding the optimal therapy selection and treatment strategy for individual patients, which might be eventually overcome by current intensive efforts in biomarker research. That work includes evaluation of tumour cell PD-L1 expression, gene expression signatures, CD8+ T cell density and others. In the future, further advances in the understanding of immune checkpoint biology might reveal new therapeutic targets beyond PD-1, PD-L1 and CTLA-4, as well as new combination approaches.
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Affiliation(s)
- Wenxin Xu
- Beth Israel Deaconess Medical Center, Boston, MA, USA
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31
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Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol 2020; 21:105-120. [PMID: 31753727 PMCID: PMC6946880 DOI: 10.1016/s1470-2045(19)30668-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. METHODS We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. FINDINGS Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. INTERPRETATION Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. FUNDING Eli Lilly and Company.
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Affiliation(s)
| | | | - Kim N Chi
- British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Alexandra Drakaki
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | | | | | | | - Syed A Hussain
- Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK
| | | | | | - Evan Y Yu
- University of Washington, Seattle, WA, USA
| | | | | | - Boris Alekseev
- P.A. Herzen Moscow Oncological Research Institute, Moscow, Russia
| | - Andrea Necchi
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Lajos Géczi
- National Institute of Oncology, Budapest, Hungary
| | - Yen-Chuan Ou
- Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan
| | | | - Wen-Pin Su
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University & Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jens Bedke
- Department of Urology, University of Tübingen, Tübingen, Germany
| | - Georgios Gakis
- Department of Urology, University of Tübingen, Tübingen, Germany; Pediatric Urology, Julius Maximillians University, Würzburg, Germany
| | | | - Jae-Lyun Lee
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Marcello Tucci
- Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Turin, Italy
| | - Andrey Semenov
- RBHI Ivanovo Regional Oncology Dispensary, Ivanovo, Russia
| | | | | | - Giampaolo Tortora
- University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | | | - Xavier Garcia Del Muro
- Institut Català d'Oncologia L'Hospitalet, Institut d'Investigacio Biomedica de Bellvitge, University of Barcelona, Barcelona, Spain
| | | | | | | | - Scott T Tagawa
- New York-Presbyterian/Weill Cornell Medical Center, New York, NY, USA
| | | | | | - Oday Hamid
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | | | | | | | | | - Thomas Powles
- Barts Cancer Institute, Queen Mary University of London, London, UK
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32
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George S, Rini BI, Hammers HJ. Emerging Role of Combination Immunotherapy in the First-line Treatment of Advanced Renal Cell Carcinoma: A Review. JAMA Oncol 2019; 5:411-421. [PMID: 30476955 DOI: 10.1001/jamaoncol.2018.4604] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Importance Novel immunotherapies, notably the immune checkpoint inhibitors, have been shown to be efficacious in patients with advanced renal cell carcinoma, but innate or adaptive resistance is observed with single-agent immunotherapy. New combination treatment strategies are needed that can improve efficacy in a broader patient population, without exacerbating the toxic effects. Observations Numerous late-phase trials are ongoing to investigate (1) dual immune checkpoint inhibition or (2) combined inhibition of immune checkpoints and vascular endothelial growth factor. Initial results from studies of the nivolumab plus ipilimumab and atezolizumab plus bevacizumab combinations have demonstrated efficacy compared with sunitinib malate in treatment-naïve patients with advanced renal cell carcinoma; moreover, the safety profile of these combinations compare favorably with sunitinib. Nevertheless, immune checkpoint inhibition is associated with unique immune-related adverse events, and practicing physicians must be educated on how to best identify and manage these events. Conclusions and Relevance Evidence suggests that immunotherapy-based combination regimens will be an important addition to the treatment of advanced renal cell carcinoma in both the first- and later-line setting; however, clinical study data and clinical practice experience indicate that optimizing the management of the associated immune-related adverse events is essential to maximizing the advantages of these therapies.
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Affiliation(s)
- Saby George
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Brian I Rini
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
| | - Hans J Hammers
- Department of Internal Medicine, UT Southwestern, Kidney Cancer Program, Dallas, Texas
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33
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Gao L, Yang X, Yi C, Zhu H. Adverse Events of Concurrent Immune Checkpoint Inhibitors and Antiangiogenic Agents: A Systematic Review. Front Pharmacol 2019; 10:1173. [PMID: 31680957 PMCID: PMC6812341 DOI: 10.3389/fphar.2019.01173] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 09/12/2019] [Indexed: 02/05/2023] Open
Abstract
Background: Immune checkpoint blockade has revolutionized the treatment of multiple malignancies. Currently, however, the effect is not universal, with objective response rates (ORR) of about 15–25%, and even lower for some cancers. Abnormal vasculature is a hallmark of most solid tumors and plays a role in immune evasion. Growing body of evidence suggests that vascular normalization and immune reprogramming could operate synergistic effect, resulting in an enhanced therapeutic efficacy. However, the benefit of antitumor efficacy must be weighed against the risk of added toxicity. In this systematic review, we summarize severe toxicity observed in such a kind of combination regimen. Methods: PubMed and Embase were searched for English references published up to May 31, 2019, with MeSH and keywords search terms of immune checkpoint inhibitors (ICIs) and antiangiogenic agents approved for using in solid tumors. Studies performing concomitant use of ICIs and antiangiogenic agents, and also reporting severe treatment-related adverse events (trAEs) (≥grade 3), were included for further analysis. Results: A total of 32 studies including a total of 2,324 participants were analyzed. Limited available data suggests that both antiangiogenic monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) show potential risk of increasing treatment-related toxicity when combined with ICIs. Overall, the total incidence of severe adverse events (AEs) associated with ICIs plus mAbs (44.5%) is lower than that of ICIs plus TKIs (60.1%). However, the trAEs observed in combination therapy are mostly consistent with the known safety profiles of corresponding monotherapy, and they seem to be largely related to antiangiogenic agents, rather than a true immune-related adverse event (irAE) predominantly due to ICIs. The majority of trAEs are intervened by holding ICI treatment and adding corticosteroids, as well as reducing dose or adjusting administration frequency of the antiangiogenic drugs. Conclusions: Concurrent use of ICIs and antiangiogenic agents shows potential treatment-related toxicity. Further research is required to compare the efficacy and safety of the combination regimen and corresponding monotherapy and identify predictive biomarkers, as well as explore dose, duration, and sequencing schedules of drugs.
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Affiliation(s)
- Ling Gao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng Yi
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Stühler V, Maas JM, Rausch S, Stenzl A, Bedke J. Immune checkpoint inhibition for the treatment of renal cell carcinoma. Expert Opin Biol Ther 2019; 20:83-94. [PMID: 31587590 DOI: 10.1080/14712598.2020.1677601] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Introduction: The systemic therapy in metastatic renal cell carcinoma (mRCC) is moving from tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors to immune checkpoint inhibitors and its combination with TKIs.Areas covered: This review provides a general overview using immune checkpoint inhibition for the treatment of RCC. Clinical results from conducted and ongoing clinical trials are summarized and checkpoint inhibition is reviewed in the context to other available systemic therapies such as TKIs for mRCC based on the different International Metastastic RCC Database Consortium (IMCD) risk groups. Furthermore, prospects for the use of predictive biomarkers in the decision-making process of chosen therapy will be given.Expert opinion: Using checkpoint inhibition in mRCC has demonstrated a superior efficacy for patients with IMDC intermediate and poor risk for ipilimumab combined with nivolumab. Furthermore, therapeutic regimes with tyrosine kinase inhibition plus immune checkpoint-inhibition were recently presented and demonstrated superiority in all risk groups for axitinib plus pembrolizumab in overall survival and progression-free survival (PFS) and axitinib plus avelumab in PFS compared to sunitinib monotherapy. Novel biomarkers of response to further optimize therapeutic selection and patient outcomes are ongoing medical objectives.
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Affiliation(s)
- Viktoria Stühler
- Department of Urology, University of Tübingen, Tübingen, Germany
| | - Jan Moritz Maas
- Department of Urology, University of Tübingen, Tübingen, Germany
| | - Steffen Rausch
- Department of Urology, University of Tübingen, Tübingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University of Tübingen, Tübingen, Germany
| | - Jens Bedke
- Department of Urology, University of Tübingen, Tübingen, Germany
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Xu W, Puligandla M, Manola J, Bullock AJ, Tamasauskas D, McDermott DF, Atkins MB, Haas NB, Flaherty K, Uzzo RG, Dutcher JP, DiPaola RS, Bhatt RS. Angiogenic Factor and Cytokine Analysis among Patients Treated with Adjuvant VEGFR TKIs in Resected Renal Cell Carcinoma. Clin Cancer Res 2019; 25:6098-6106. [PMID: 31471309 DOI: 10.1158/1078-0432.ccr-19-0818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/06/2019] [Accepted: 07/09/2019] [Indexed: 12/30/2022]
Abstract
PURPOSE The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial. EXPERIMENTAL DESIGN Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels. RESULTS VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib (P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib (P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib (P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status. CONCLUSIONS Among patients treated with adjuvant VEGFR TKIs for RCC, drug-host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.
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Affiliation(s)
- Wenxin Xu
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Maneka Puligandla
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | - Judith Manola
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | | | | | | | - Michael B Atkins
- MedStar Georgetown University Hospital, Washington, District of Columbia
| | - Naomi B Haas
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | | | | | - Rupal S Bhatt
- Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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Ingles Garces AH, Au L, Mason R, Thomas J, Larkin J. Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer. Expert Opin Investig Drugs 2019; 28:695-708. [DOI: 10.1080/13543784.2019.1649657] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
| | - Lewis Au
- The Royal Marsden NHS Foundation Trust, London, UK
| | - Robert Mason
- The Royal Marsden NHS Foundation Trust, London, UK
| | | | - James Larkin
- The Royal Marsden NHS Foundation Trust, London, UK
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Safety and Tolerability of Anti-Angiogenic Protein Kinase Inhibitors and Vascular-Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies. Drug Saf 2019; 42:159-179. [PMID: 30649744 DOI: 10.1007/s40264-018-0776-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.
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Pilié PG, Jonasch E. Durable complete response in renal cell carcinoma clinical trials. Lancet 2019; 393:2362-2364. [PMID: 31079937 DOI: 10.1016/s0140-6736(19)30949-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 04/09/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Patrick G Pilié
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Eric Jonasch
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Affiliation(s)
- Iris Y. Sheng
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
| | - Brian I. Rini
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
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Angelova A, Rommelaere J. Immune System Stimulation by Oncolytic Rodent Protoparvoviruses. Viruses 2019; 11:E415. [PMID: 31060205 PMCID: PMC6563271 DOI: 10.3390/v11050415] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 04/29/2019] [Accepted: 05/02/2019] [Indexed: 01/10/2023] Open
Abstract
Rodent protoparvoviruses (PVs), parvovirus H-1 (H-1PV) in particular, are naturally endowed with oncolytic properties. While being historically described as agents that selectively replicate in and kill cancer cells, recent yet growing evidence demonstrates that these viruses are able to reverse tumor-driven immune suppression through induction of immunogenic tumor cell death, and the establishment of antitumorigenic, proinflammatory milieu within the tumor microenvironment. This review summarizes the most important preclinical proofs of the interplay and the cooperation between PVs and the host immune system. The molecular mechanisms of PV-induced immunostimulation are also discussed. Furthermore, initial encouraging in-human observations from clinical trials and compassionate virus uses are presented, and speak in favor of further H-1PV clinical development as partner drug in combined immunotherapeutic protocols.
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Affiliation(s)
- Assia Angelova
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Jean Rommelaere
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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de Goeje PL, Poncin M, Bezemer K, Kaijen-Lambers MEH, Groen HJM, Smit EF, Dingemans AMC, Kunert A, Hendriks RW, Aerts JGJV. Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non-small Cell Lung Cancer Patients. Clin Cancer Res 2019; 25:2219-2227. [PMID: 30642911 DOI: 10.1158/1078-0432.ccr-18-2243] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 12/03/2018] [Accepted: 01/10/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Chemotherapy has long been the standard treatment for advanced stage non-small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immune-modulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on the immune populations associated with the response to checkpoint inhibitors in peripheral blood. EXPERIMENTAL DESIGN A total of 223 patients with stage IV NSCLC, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin patch. Peripheral blood was collected at baseline and after the first and second treatment cycle, proportions of T cells, B cells, and monocytes were determined by flow cytometry. Furthermore, several subsets of T cells and the expression of Ki67 and coinhibitory receptors on these subsets were determined. RESULTS Although proliferation of CD4 T cells remained stable following treatment, proliferation of peripheral blood CD8 T cells was significantly increased, particularly in the effector memory and CD45RA+ effector subsets. The proliferating CD8 T cells more highly expressed programmed death receptor (PD)-1 and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) compared with nonproliferating CD8 T cells. Immunologic responders (iR; >2 fold increased proliferation after treatment) did not show an improved progression-free (PFS) or overall survival (OS). CONCLUSIONS Paclitaxel/carboplatin/bevacizumab induces proliferation of CD8 T cells, consisting of effector cells expressing coinhibitory checkpoint molecules. Induction of proliferation was not correlated to clinical outcome in the current clinical setting. Our findings provide a rationale for combining PCB with checkpoint inhibition in lung cancer.
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Affiliation(s)
- Pauline L de Goeje
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Myrthe Poncin
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Koen Bezemer
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Margaretha E H Kaijen-Lambers
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Harry J M Groen
- Groningen University Medical Center, Department of Respiratory Disease, Groningen, the Netherlands
| | - Egbert F Smit
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Anne-Marie C Dingemans
- Department of Respiratory Disease, Maastricht University Medical Center, Maastricht, the Netherlands
| | - André Kunert
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Rotterdam, the Netherlands.,Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Joachim G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. .,Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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Wallace K, Lewin DN, Sun S, Spiceland CM, Rockey DC, Alekseyenko AV, Wu JD, Baron JA, Alberg AJ, Hill EG. Tumor-Infiltrating Lymphocytes and Colorectal Cancer Survival in African American and Caucasian Patients. Cancer Epidemiol Biomarkers Prev 2018; 27:755-761. [PMID: 29769214 PMCID: PMC6449046 DOI: 10.1158/1055-9965.epi-17-0870] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 12/08/2017] [Accepted: 05/08/2018] [Indexed: 12/11/2022] Open
Abstract
Background: Compared with Caucasian Americans (CAs), African Americans (AAs) with colorectal cancer have poorer survival, especially younger-age patients. A robust lymphocytic reaction within colorectal cancers is strongly associated with better survival, but whether immune response impacts the disparity in colorectal cancer survival is unknown.Methods: The study population was comprised of 211 histologically confirmed colorectal cancers at the Medical University of South Carolina (Charleston, SC; 159 CAs and 52 AAs) diagnosed between Jan 01, 2000, and June 30, 2013. We constructed a lymphocyte score based on blinded pathologic assessment of the four different types of lymphocytic reactions. Cox proportional hazards regression was used to evaluate the association between the lymphocyte score and risk of death by race.Results: Colorectal cancers in AAs (vs. CAs) had a stronger lymphocytic reaction at diagnosis. A high lymphocyte score (vs. the lowest) was associated with better survival in AAs [HR 0.19; 95% confidence interval (CI), 0.04-0.99] and CAs (HR 0.47; 95% CI, 0.15-1.45). AAs with no lymphocytic reaction (vs. other categories) had poor survival HR 4.48 (1.58-12.7) whereas no difference was observed in CAs. The risk of death in AAs (vs. CA) was more pronounced in younger patients (HR 2.92; 95% CI, 1.18-7.22) compared with older (HR 1.20; 95% CI, 0.54-2.67), especially those with lymphocytic poor colorectal cancers.Conclusions: The lymphocytic reaction in tumor impacted the racial disparity in survival.Impact: Our results confirm the importance of the lymphocytic score on survival and highlight the need to fully characterize the immune environment of colorectal cancers by race. Cancer Epidemiol Biomarkers Prev; 27(7); 755-61. ©2018 AACR.
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Affiliation(s)
- Kristin Wallace
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - David N Lewin
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Shaoli Sun
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Clayton M Spiceland
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Don C Rockey
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Alexander V Alekseyenko
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Jennifer D Wu
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - John A Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Anthony J Alberg
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Elizabeth G Hill
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
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Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018; 24:749-757. [PMID: 29867230 DOI: 10.1038/s41591-018-0053-3] [Citation(s) in RCA: 936] [Impact Index Per Article: 133.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 03/30/2018] [Indexed: 02/06/2023]
Abstract
We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
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Mackay A, Burford A, Molinari V, Jones DTW, Izquierdo E, Brouwer-Visser J, Giangaspero F, Haberler C, Pietsch T, Jacques TS, Figarella-Branger D, Rodriguez D, Morgan PS, Raman P, Waanders AJ, Resnick AC, Massimino M, Garrè ML, Smith H, Capper D, Pfister SM, Würdinger T, Tam R, Garcia J, Thakur MD, Vassal G, Grill J, Jaspan T, Varlet P, Jones C. Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell 2018; 33:829-842.e5. [PMID: 29763623 PMCID: PMC5956280 DOI: 10.1016/j.ccell.2018.04.004] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/28/2018] [Accepted: 04/10/2018] [Indexed: 12/30/2022]
Abstract
The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population.
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Affiliation(s)
- Alan Mackay
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | - Anna Burford
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | - Valeria Molinari
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | - David T W Jones
- Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elisa Izquierdo
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | | | - Felice Giangaspero
- Department of Radiology, Oncology and Anatomic-Pathology Sciences, Sapienza University, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy
| | - Christine Haberler
- Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Torsten Pietsch
- DGNN Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany
| | - Thomas S Jacques
- UCL Great Ormond Street Institute of Child Health, London, UK; Department of Histopathology, Great Ormond Street Hospital for Children, London, UK
| | | | | | | | - Pichai Raman
- The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Angela J Waanders
- The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Adam C Resnick
- The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Maura Massimino
- Pediatric Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy
| | | | - Helen Smith
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - David Capper
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Institute of Neuropathology, Berlin, Germany; Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan M Pfister
- Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Würdinger
- Department of Neurosurgery, Brain Tumor Center Amsterdam, VU Medical Center, Amsterdam, the Netherlands
| | | | | | | | - Gilles Vassal
- Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Jacques Grill
- Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Tim Jaspan
- Nottingham University Hospitals, Nottingham, UK
| | - Pascale Varlet
- Sainte-Anne Hospital, Paris-Descartes University, Paris, France
| | - Chris Jones
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK.
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Battaglin F, Puccini A, Intini R, Schirripa M, Ferro A, Bergamo F, Lonardi S, Zagonel V, Lenz HJ, Loupakis F. The role of tumor angiogenesis as a therapeutic target in colorectal cancer. Expert Rev Anticancer Ther 2018; 18:251-266. [PMID: 29338550 PMCID: PMC7493706 DOI: 10.1080/14737140.2018.1428092] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 01/11/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Angiogenesis is a complex process regulated by several pro- and anti-angiogenic factors, thus the loss of its fine equilibrium plays a key role in colorectal cancer (CRC) development and progression. Therapeutic agents targeting VEGF/VEGFR signaling, the main regulator of this process, proved to be effective across different treatment lines in metastatic CRC (mCRC) and contributed greatly to improve patients' survival in recent years. Areas covered: This review aimed to summarize the actual body of knowledge available on the VEGF pathway in CRC, including currently available anti-angiogenic drugs and treatment challenges, mechanisms of resistance, promising predictive biomarkers and future perspectives. Expert commentary: Angiogenesis inhibition in subsequent lines of treatment is a valid strategy in the continuum of care of mCRC patients. In this scenario, the availability of multiple agents warrants to tailor therapy to an individualized approach. However, the validation of predictive biomarkers to aid therapeutic decisions remains an issue. Intrinsic and adaptive resistance to anti-angiogenic agents comprises distinct and intertwined processes, eventually leading to treatment failure and disease progression. The expanding knowledge on the mechanisms underlying the angiogenesis pathway, different potential treatment targets and mechanisms of tumor resistance, may lead to promising new perspectives in this field.
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Affiliation(s)
- Francesca Battaglin
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Medical Oncology 1, Ospedale Policlinico San Martino, Genova, Italy
| | - Rossana Intini
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Marta Schirripa
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Alessandra Ferro
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Francesca Bergamo
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Vittorina Zagonel
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fotios Loupakis
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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NUEVAS TERAPIAS EN EL MANEJO DE LOS GLIOMAS DE ALTO GRADO. REVISTA MÉDICA CLÍNICA LAS CONDES 2017. [DOI: 10.1016/j.rmclc.2017.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Malek E, de Lima M, Letterio JJ, Kim BG, Finke JH, Driscoll JJ, Giralt SA. Myeloid-derived suppressor cells: The green light for myeloma immune escape. Blood Rev 2016; 30:341-8. [PMID: 27132116 DOI: 10.1016/j.blre.2016.04.002] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 03/28/2016] [Accepted: 04/01/2016] [Indexed: 01/04/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress innate and adaptive immune responses that promote tumor growth. MDSCs are increased in patients with multiple myeloma (MM) and have bidirectional interaction with tumors within the MM microenvironment. MM-MDSCs promote MM tumor growth and induce immune suppression; conversely, MM cells induce MDSC development and survival. Although the role of MDSCs in infections, inflammatory diseases and solid tumors has been extensively characterized, their tumor-promoting and immune-suppressive role in MM and the MM microenvironment is only beginning to emerge. The presence and activation of MDSCs in MM patients has been well documented; however, the direct actions and functional consequences of MDSCs on cancer cells is poorly defined. Immunosuppressive MDSCs play an important role in tumor progression primarily because of their capability to promote immune-escape, angiogenesis, drug resistance and metastasis. However, their role in the bone marrow (BM), the primary MM site, is poorly understood. MM remains an incurable malignancy, and it is likely that the BM microenvironment protects MM against chemotherapy agents and the host immune system. A growing body of evidence suggests that host immune cells with a suppressive phenotype contribute to a myeloma immunosuppressive network. Among the known suppressor cells, MDSCs and T regulatory cells (Tregs) have been found to be significantly increased in myeloma patients and their levels correlate with disease stage and clinical outcome. Furthermore, it has been shown that MDSC can mediate suppression of myeloma-specific T-cell responses through the induction of T-cell anergy and Treg development in the MM microenvironment. Here, we review clinical correlations and the preclinical proof-of-principle data on the role of MDSCs in myeloma immunotolerance and highlight the mechanistically relevant MDSC-targeted compounds and their potential utility in a new approach for anti-myeloma therapy.
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Affiliation(s)
- Ehsan Malek
- University Hospitals Case Medical Center, Seidman Cancer Center, Cleveland, OH, USA.
| | - Marcos de Lima
- University Hospitals Case Medical Center, Seidman Cancer Center, Cleveland, OH, USA
| | - John J Letterio
- Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA; The Angie Fowler Adolescent & Young Adult Cancer Institute, Rainbow Babies & Children's Hospital, University Hospitals, Cleveland, OH, USA
| | - Byung-Gyu Kim
- Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA; The Angie Fowler Adolescent & Young Adult Cancer Institute, Rainbow Babies & Children's Hospital, University Hospitals, Cleveland, OH, USA
| | - James H Finke
- Taussig Cancer Institute, Glickman Urological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - James J Driscoll
- Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sergio A Giralt
- Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Konda B, Shum H, Rajdev L. Anti-angiogenic agents in metastatic colorectal cancer. World J Gastrointest Oncol 2015; 7:71-86. [PMID: 26191351 PMCID: PMC4501927 DOI: 10.4251/wjgo.v7.i7.71] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/13/2015] [Accepted: 06/01/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various anti-angiogenic agents in patients with metastatic CRC (mCRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in mCRC patients. Despite the discovery of several promising anti-angiogenic agents, mCRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.
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