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1
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Rollins ZA, Curtis MB, George SC, Faller R. A Computational Strategy for the Rapid Identification and Ranking of Patient-Specific T Cell Receptors Bound to Neoantigens. Macromol Rapid Commun 2024; 45:e2400225. [PMID: 38839076 PMCID: PMC11661661 DOI: 10.1002/marc.202400225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/02/2024] [Indexed: 06/07/2024]
Abstract
T cell receptor (TCR) recognition of a peptide-major histocompatibility complex (pMHC) is crucial for adaptive immune response. The identification of therapeutically relevant TCR-pMHC protein pairs is a bottleneck in the implementation of TCR-based immunotherapies. The ability to computationally design TCRs to target a specific pMHC requires automated integration of next-generation sequencing, protein-protein structure prediction, molecular dynamics, and TCR ranking. A pipeline to evaluate patient-specific, sequence-based TCRs to a target pMHC is presented. Using the three most frequently expressed TCRs from 16 colorectal cancer patients, the protein-protein structure of the TCRs to the target CEA peptide-MHC is predicted using Modeller and ColabFold. TCR-pMHC structures are compared using automated equilibration and successive analysis. ColabFold generated configurations require an ≈2.5× reduction in equilibration time of TCR-pMHC structures compared to Modeller. The structural differences between Modeller and ColabFold are demonstrated by root mean square deviation (≈0.20 nm) between clusters of equilibrated configurations, which impact the number of hydrogen bonds and Lennard-Jones contacts between the TCR and pMHC. TCR ranking criteria that may prioritize TCRs for evaluation of in vitro immunogenicity are identified, and this ranking is validated by comparing to state-of-the-art machine learning-based methods trained to predict the probability of TCR-pMHC binding.
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Affiliation(s)
- Zachary A. Rollins
- Department of Chemical EngineeringUniversity of CaliforniaDavis, 1 Shields Ave, Bainer HallDavisCA95616USA
| | - Matthew B. Curtis
- Department of Biomedical EngineeringUniversity of CaliforniaDavis, 451 E. Health Sciences Dr., GBSF 2303DavisCA95616USA
| | - Steven C. George
- Department of Biomedical EngineeringUniversity of CaliforniaDavis, 451 E. Health Sciences Dr., GBSF 2303DavisCA95616USA
| | - Roland Faller
- Department of Chemical EngineeringUniversity of CaliforniaDavis, 1 Shields Ave, Bainer HallDavisCA95616USA
- Department of Chemical EngineeringTexas Tech UniversityLubbockTX79409USA
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2
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Bhagat A, Lyerly HK, Morse MA, Hartman ZC. CEA vaccines. Hum Vaccin Immunother 2023; 19:2291857. [PMID: 38087989 PMCID: PMC10732609 DOI: 10.1080/21645515.2023.2291857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 12/02/2023] [Indexed: 12/18/2023] Open
Abstract
Carcinoembryonic antigen (CEA) is a glycosylated cell surface oncofetal protein involved in adhesion, proliferation, and migration that is highly upregulated in multiple carcinomas and has long been a promising target for cancer vaccination. This review summarizes the progress to date in the development of CEA vaccines, examining both pre-clinical and clinical studies across a variety of vaccine platforms that in aggregate, begin to reveal some critical insights. These studies demonstrate the ability of CEA vaccines to break immunologic tolerance and elicit CEA-specific immunity, which associates with improved clinical outcomes in select individuals. Approaches that have combined replicating viral vectors, with heterologous boosting and different adjuvant strategies have been particularly promising but, these early clinical trial results will require confirmatory studies. Collectively, these studies suggest that clinical efficacy likely depends upon harnessing a potent vaccine combination in an appropriate clinical setting to fully realize the potential of CEA vaccination.
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Affiliation(s)
- Anchit Bhagat
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
| | - Herbert K. Lyerly
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
- Department of Pathology, Duke University, Durham, NC, USA
- Department of Integrative Immunobiology, Duke University, Durham, NC, USA
| | - Michael A. Morse
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
- Department of Medicine, Duke University, Durham, NC, USA
| | - Zachary C. Hartman
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
- Department of Pathology, Duke University, Durham, NC, USA
- Department of Integrative Immunobiology, Duke University, Durham, NC, USA
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3
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Seclì L, Leoni G, Ruzza V, Siani L, Cotugno G, Scarselli E, D’Alise AM. Personalized Cancer Vaccines Go Viral: Viral Vectors in the Era of Personalized Immunotherapy of Cancer. Int J Mol Sci 2023; 24:16591. [PMID: 38068911 PMCID: PMC10706435 DOI: 10.3390/ijms242316591] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/17/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
The aim of personalized cancer vaccines is to elicit potent and tumor-specific immune responses against neoantigens specific to each patient and to establish durable immunity, while minimizing the adverse events. Over recent years, there has been a renewed interest in personalized cancer vaccines, primarily due to the advancement of innovative technologies for the identification of neoantigens and novel vaccine delivery platforms. Here, we review the emerging field of personalized cancer vaccination, with a focus on the use of viral vectors as a vaccine platform. The recent advancements in viral vector technology have led to the development of efficient production processes, positioning personalized viral vaccines as one of the preferred technologies. Many clinical trials have shown the feasibility, safety, immunogenicity and, more recently, preliminary evidence of the anti-tumor activity of personalized vaccination, fostering active research in the field, including further clinical trials for different tumor types and in different clinical settings.
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Affiliation(s)
| | | | | | | | | | | | - Anna Morena D’Alise
- Nouscom, Via di Castel Romano 100, 00128 Rome, Italy; (L.S.); (G.L.); (V.R.); (L.S.); (G.C.); (E.S.)
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4
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Recent Advances in Cancer Vaccines: Challenges, Achievements, and Futuristic Prospects. Vaccines (Basel) 2022; 10:vaccines10122011. [PMID: 36560420 PMCID: PMC9788126 DOI: 10.3390/vaccines10122011] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is a chronic disease, and it can be lethal due to limited therapeutic options. The conventional treatment options for cancer have numerous challenges, such as a low blood circulation time as well as poor solubility of anticancer drugs. Therapeutic cancer vaccines emerged to try to improve anticancer drugs' efficiency and to deliver them to the target site. Cancer vaccines are considered a viable therapeutic technique for most solid tumors. Vaccines boost antitumor immunity by delivering tumor antigens, nucleic acids, entire cells, and peptides. Cancer vaccines are designed to induce long-term antitumor memory, causing tumor regression, eradicate minimal residual illness, and prevent non-specific or unpleasant effects. These vaccines can assist in the elimination of cancer cells from various organs or organ systems in the body, with minimal risk of tumor recurrence or metastasis. Vaccines and antigens for anticancer therapy are discussed in this review, including current vaccine adjuvants and mechanisms of action for various types of vaccines, such as DNA- or mRNA-based cancer vaccines. Potential applications of these vaccines focusing on their clinical use for better therapeutic efficacy are also discussed along with the latest research available in this field.
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5
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Li B. Why do tumor-infiltrating lymphocytes have variable efficacy in the treatment of solid tumors? Front Immunol 2022; 13:973881. [PMID: 36341370 PMCID: PMC9635507 DOI: 10.3389/fimmu.2022.973881] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/14/2022] [Indexed: 07/30/2023] Open
Abstract
Lymphocytes in tumor tissue are called tumor-infiltrating lymphocytes (TILs), and they play a key role in the control and treatment of tumor diseases. Since the discovery in 1987 that cultured TILs can kill tumor cells more than 100 times more effectively than T-cells cultured from peripheral blood in melanoma, it has been confirmed that cultured TILs can successfully cure clinical patients with melanoma. Since 1989, after we investigated TIL isolation performance from solid tumors, we modified some procedures to increase efficacy, and thus successfully established new TIL isolation and culture methods in 1994. Moreover, our laboratory and clinicians using our cultured TILs have published more than 30 papers. To improve the efficacy of TILs, we have been carrying out studies of TIL efficacy to treat solid tumor diseases for approximately 30 years. The three main questions of TIL study have been "How do TILs remain silent in solid tumor tissue?", "How do TILs attack homologous and heterologous antigens from tumor cells of solid tumors?", and "How do TILs infiltrate solid tumor tissue from a distance into tumor sites to kill tumor cells?". Research on these three issues has increasingly answered these questions. In this review I summarize the main issues surrounding TILs in treating solid tumors. This review aims to study the killing function of TILs from solid tumor tissues, thereby ultimately introducing the optimal strategy for patients suffering from solid tumors through personalized immunotherapy in the near future.
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Affiliation(s)
- Biaoru Li
- Georgia Cancer Center and Department of Pediatrics, Medical College at Georgia (GA), Augusta, GA, United States
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6
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Alarcon NO, Jaramillo M, Mansour HM, Sun B. Therapeutic Cancer Vaccines—Antigen Discovery and Adjuvant Delivery Platforms. Pharmaceutics 2022; 14:pharmaceutics14071448. [PMID: 35890342 PMCID: PMC9325128 DOI: 10.3390/pharmaceutics14071448] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 12/15/2022] Open
Abstract
For decades, vaccines have played a significant role in protecting public and personal health against infectious diseases and proved their great potential in battling cancers as well. This review focused on the current progress of therapeutic subunit vaccines for cancer immunotherapy. Antigens and adjuvants are key components of vaccine formulations. We summarized several classes of tumor antigens and bioinformatic approaches of identification of tumor neoantigens. Pattern recognition receptor (PRR)-targeting adjuvants and their targeted delivery platforms have been extensively discussed. In addition, we emphasized the interplay between multiple adjuvants and their combined delivery for cancer immunotherapy.
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Affiliation(s)
- Neftali Ortega Alarcon
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Maddy Jaramillo
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
| | - Heidi M. Mansour
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- Department of Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
| | - Bo Sun
- Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (N.O.A.); (M.J.); (H.M.M.)
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA
- Correspondence: ; Tel.: +1-520-621-6420
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7
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Xu R, Du S, Zhu J, Meng F, Liu B. Neoantigen-targeted TCR-T cell therapy for solid tumors: How far from clinical application. Cancer Lett 2022; 546:215840. [DOI: 10.1016/j.canlet.2022.215840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/09/2022] [Accepted: 07/22/2022] [Indexed: 11/25/2022]
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8
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Zhang L, Zhou X, Sha H, Xie L, Liu B. Recent Progress on Therapeutic Vaccines for Breast Cancer. Front Oncol 2022; 12:905832. [PMID: 35734599 PMCID: PMC9207208 DOI: 10.3389/fonc.2022.905832] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer remains the most frequently diagnosed malignancy worldwide. Advanced breast cancer is still an incurable disease mainly because of its heterogeneity and limited immunogenicity. The great success of cancer immunotherapy is paving the way for a new era in cancer treatment, and therapeutic cancer vaccination is an area of interest. Vaccine targets include tumor-associated antigens and tumor-specific antigens. Immune responses differ in different vaccine delivery platforms. Next-generation sequencing technologies and computational analysis have recently made personalized vaccination possible. However, only a few cases benefiting from neoantigen-based treatment have been reported in breast cancer, and more attention has been given to overexpressed antigen-based treatment, especially human epidermal growth factor 2-derived peptide vaccines. Here, we discuss recent advancements in therapeutic vaccines for breast cancer and highlight near-term opportunities for moving forward.
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Affiliation(s)
- Lianru Zhang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Xipeng Zhou
- Department of oncology, Yizheng People's Hospital, Yangzhou, China
| | - Huizi Sha
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Li Xie
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China
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9
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Vaccines in Gastrointestinal Malignancies: From Prevention to Treatment. Vaccines (Basel) 2021; 9:vaccines9060647. [PMID: 34199248 PMCID: PMC8231997 DOI: 10.3390/vaccines9060647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal (GI) malignancies are some of the most common and devastating malignancies and include colorectal, gastric, esophageal, hepatocellular, and pancreatic carcinomas, among others. Five-year survival rates for many of these malignancies remain low. The majority presents at an advanced stage with limited treatment options and poor overall survival. Treatment is advancing but not at the same speed as other malignancies. Chemotherapy and radiation treatments are still only partially effective in GI malignancies and cause significant side effects. Thus, there is an urgent need for novel strategies in the treatment of GI malignancies. Recently, immunotherapy and checkpoint inhibitors have entered as potential new therapeutic options for patients, and thus, cancer vaccines may play a major role in the future of treatment for these malignancies. Further advances in understanding the interaction between the tumor and immune system have led to the development of novel agents, such as cancer vaccines.
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10
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Bonilla WV, Kirchhammer N, Marx AF, Kallert SM, Krzyzaniak MA, Lu M, Darbre S, Schmidt S, Raguz J, Berka U, Vincenti I, Pauzuolis M, Kerber R, Hoepner S, Günther S, Magnus C, Merkler D, Orlinger KK, Zippelius A, Pinschewer DD. Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack. CELL REPORTS MEDICINE 2021; 2:100209. [PMID: 33763654 PMCID: PMC7974551 DOI: 10.1016/j.xcrm.2021.100209] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/16/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
Abstract
Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.
Engineered arenaviruses induce potent tumor self-specific CD8 T cell (CTL) response Combinations of distantly but not closely related arenavirus vectors eliminate tumors Vector backbone-targeted CTL responses compete against tumor self-reactive CTLs Optimized vector combinations reshuffle immunodominance to break self-tolerance
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Affiliation(s)
- Weldy V Bonilla
- University of Basel, Department of Biomedicine, Basel, Switzerland
| | | | | | - Sandra M Kallert
- University of Basel, Department of Biomedicine, Basel, Switzerland
| | | | - Min Lu
- University of Basel, Department of Biomedicine, Basel, Switzerland
| | - Stéphanie Darbre
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | | | | | | | - Ilena Vincenti
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Mindaugas Pauzuolis
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Romy Kerber
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Sabine Hoepner
- Tumor Immunology, Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Stephan Günther
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Carsten Magnus
- Institute of Virology, University of Zurich, Zurich, Switzerland
| | - Doron Merkler
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland
| | | | - Alfred Zippelius
- University of Basel, Department of Biomedicine, Basel, Switzerland.,Medical Oncology, University Hospital Basel, Basel, Switzerland
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11
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Benvenuto M, Focaccetti C, Izzi V, Masuelli L, Modesti A, Bei R. Tumor antigens heterogeneity and immune response-targeting neoantigens in breast cancer. Semin Cancer Biol 2019; 72:65-75. [PMID: 31698088 DOI: 10.1016/j.semcancer.2019.10.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/30/2019] [Indexed: 12/25/2022]
Abstract
Breast cancer is both the most common type of cancer and the most frequent cause of cancer mortality in women, mainly because of its heterogeneity and limited immunogenicity. The aim of specific active cancer immunotherapy is to stimulate the host's immune response against cancer cells directly using a vaccine platform carrying one or more tumor antigens. In particular, the ideal tumor antigen should be able to elicit T cell and B cell responses, be specific for the tumor and be expressed at high levels on cancer cells. Neoantigens are ideal targets for immunotherapy because they are exclusive to individual patient's tumors, are absent in healthy tissues and are not subject to immune tolerance mechanisms. Thus, neoantigens should generate a specific reaction towards tumors since they constitute the largest fraction of targets of tumor-infiltrating T cells. In this review, we describe the technologies used for neoantigen discovery, the heterogeneity of neoantigens in breast cancer and recent studies of breast cancer immunotherapy targeting neoantigens.
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Affiliation(s)
- Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy; Saint Camillus International University of Health and Medical Sciences, via di Sant'Alessandro 8, 00131, Rome, Italy.
| | - Chiara Focaccetti
- Department of Human Science and Promotion of the Quality of Life, University San Raffaele Rome, Via di Val Cannuta 247, 00166, Rome, Italy.
| | - Valerio Izzi
- Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7C, FI-90230, Oulu, Finland.
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy.
| | - Andrea Modesti
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
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12
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Gerber HP, Sibener LV, Lee LJ, Gee M. Intracellular targets as source for cleaner targets for the treatment of solid tumors. Biochem Pharmacol 2019; 168:275-284. [DOI: 10.1016/j.bcp.2019.07.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 07/12/2019] [Indexed: 01/02/2023]
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13
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Gatti-Mays ME, Strauss J, Donahue RN, Palena C, Del Rivero J, Redman JM, Madan RA, Marté JL, Cordes LM, Lamping E, Orpia A, Burmeister A, Wagner E, Pico Navarro C, Heery CR, Schlom J, Gulley JL. A Phase I Dose-Escalation Trial of BN-CV301, a Recombinant Poxviral Vaccine Targeting MUC1 and CEA with Costimulatory Molecules. Clin Cancer Res 2019; 25:4933-4944. [PMID: 31110074 DOI: 10.1158/1078-0432.ccr-19-0183] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/26/2019] [Accepted: 05/16/2019] [Indexed: 01/28/2023]
Abstract
PURPOSE BN-CV301 is a poxviral-based vaccine comprised of recombinant (rec.) modified vaccinia Ankara (MVA-BN-CV301; prime) and rec. fowlpox (FPV-CV301; boost). Like its predecessor PANVAC, BN-CV301 contains transgenes encoding tumor-associated antigens MUC1 and CEA as well as costimulatory molecules (B7.1, ICAM-1, and LFA-3). PANVAC was reengineered to make it safer and more antigenic. PATIENTS AND METHODS This open-label, 3+3 design, dose-escalation trial evaluated three dose levels (DL) of MVA-BN-CV301: one, two, or four subcutaneous injections of 4 × 108 infectious units (Inf.U)/0.5 mL on weeks 0 and 4. All patients received FPV-CV301 subcutaneously at 1 × 109 Inf.U/0.5 mL every 2 weeks for 4 doses, then every 4 weeks. Clinical and immune responses were evaluated. RESULTS There were no dose-limiting toxicities. Twelve patients enrolled on trial [dose level (DL) 1 = 3, DL2 = 3, DL3 = 6). Most side effects were seen with the prime doses and lessened with subsequent boosters. All treatment-related adverse events were temporary, self-limiting, grade 1/2, and included injection-site reactions and flu-like symptoms. Antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most patients. Single-agent BN-CV301 produced a confirmed partial response (PR) in 1 patient and prolonged stable disease (SD) in multiple patients, most notably in KRAS-mutant gastrointestinal tumors. Furthermore, 2 patients with KRAS-mutant colorectal cancer had prolonged SD when treated with an anti-PD-L1 antibody following BN-CV301. CONCLUSIONS The BN-CV301 vaccine can be safely administered to patients with advanced cancer. Further studies of the vaccine in combination with other agents are planned.See related commentary by Repáraz et al., p. 4871.
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Affiliation(s)
- Margaret E Gatti-Mays
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Julius Strauss
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Claudia Palena
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jaydira Del Rivero
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jason M Redman
- Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jennifer L Marté
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Lisa M Cordes
- Oncology Clinical Pharmacy, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Elizabeth Lamping
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Alanvin Orpia
- Leidos Biomedical Research, Inc., Frederick, Maryland
| | | | - Eva Wagner
- Bavarian Nordic GmbH, Martinsried, Germany
| | | | | | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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14
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Abstract
With the spotlight on cancer immunotherapy and the expanding use of immune checkpoint inhibitors, strategies to improve the response rate and duration of current cancer immunotherapeutics are highly sought. In that sense, investigators around the globe have been putting spurs on the development of effective cancer vaccines in humans after decades of efforts that led to limited clinical success. In more than three decades of research in pursuit of targeted and personalized immunotherapy, several platforms have been incorporated into the list of cancer vaccines from live viral or bacterial agents harboring antigens to synthetic peptides with the hope of stronger and durable immune responses that will tackle cancers better. Unlike adoptive cell therapy, cancer vaccines can take advantage of using a patient's entire immune system that can include more than engineered receptors or ligands in developing antigen-specific responses. Advances in molecular technology also secured the use of genetically modified genes or proteins of interest to enhance the chance of stronger immune responses. The formulation of vaccines to increase chances of immune recognition such as nanoparticles for peptide delivery is another area of great interest. Studies indicate that cancer vaccines alone may elicit tumor-specific cellular or humoral responses in immunologic assays and even regression or shrinkage of the cancer in select trials, but novel strategies, especially in combination with other cancer therapies, are under study and are likely to be critical to achieve and optimize reliable objective responses and survival benefit. In this review, cancer vaccine platforms with different approaches to deliver tumor antigens and boost immunity are discussed with the intention of summarizing what we know and what we need to improve in the clinical trial setting.
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Affiliation(s)
- Hoyoung M. Maeng
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jay A. Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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15
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Osipov A, Murphy A, Zheng L. From immune checkpoints to vaccines: The past, present and future of cancer immunotherapy. Adv Cancer Res 2019; 143:63-144. [PMID: 31202363 DOI: 10.1016/bs.acr.2019.03.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer is a worldwide medical problem with significant repercussions on individual patients and societies as a whole. In order to alter the outcomes of this deadly disease the treatment of cancer over the centuries has undergone a unique evolution. However, utilizing the best treatment modalities and achieving cures or long-term durable responses have been inconsistent and limited, that is until recently. Contemporary research has highlighted a fundamental gap in our understanding of how we approach treating cancer, by revealing the intricate relationship between the immune system and tumors. In this atmosphere, the growth of immunotherapy has not only forever changed our understanding of cancer biology, but the manner by which we treat patients. It's paradigm shifting success has led to the approval of over 10 different immunotherapeutic agents, including checkpoint inhibitors, vaccine-based therapies, oncolytic viruses and T cell directed therapies for nearly 20 different indications across countless tumor types. Despite the breakthroughs that have occurred in the field of immunotherapy, it has not been the panacea for all cancers. With a deeper understanding of the immune system we have been able to peer into tumor immune escape and therapy resistance. Simultaneously this understanding has paved the way for the investigation and development of novel immune system altering agents and combinatorial therapies. In this chapter we review the immune system and its intricate relationship with cancer, the evolution of immunotherapy, its current landscape, and future directions in the context of resistance mechanisms and the challenges faced by immunotherapy against cancer.
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Affiliation(s)
- Arsen Osipov
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Adrian Murphy
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lei Zheng
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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Zhang J, Wang L. The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review. Technol Cancer Res Treat 2019; 18:1533033819831068. [PMID: 30798772 PMCID: PMC6391541 DOI: 10.1177/1533033819831068] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 12/20/2018] [Accepted: 01/22/2019] [Indexed: 12/28/2022] Open
Abstract
T-cell receptor-engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chimeric antigen receptor T-cell therapy has yielded remarkable efficacy for hematological malignancies of the B-cell lineages, most solid tumors fail to respond significantly to chimeric antigen receptor T cells. T-cell receptor-engineered T-cell therapy, on the other hand, has shown unprecedented promise in treating solid tumors and has attracted growing interest. In order to create an unbiased, comprehensive, and scientific report for this fast-moving field, we carefully analyzed all 84 clinical trials using T-cell receptor-engineered T-cell therapy and downloaded from ClinicalTrials.gov updated by June 11, 2018. Informative features and trends were observed in these clinical trials. The number of trials initiated each year is increasing as expected, but an interesting pattern is observed. NY-ESO-1, as the most targeted antigen type, is the target of 31 clinical trials; melanoma is the most targeted cancer type and is the target of 33 clinical trials. Novel antigens and underrepresented cancers remain to be targeted in future studies and clinical trials. Unlike chimeric antigen receptor T-cell therapy, only about 16% of the 84 clinical trials target against hematological malignancies, consistent with T-cell receptor-engineered T-cell therapy's high potential for solid tumors. Six pharma/biotech companies with novel T-cell receptor-engineered T-cell ideas and products were examined in this review. Multiple approaches have been utilized in these companies to increase the T-cell receptor's affinity and efficiency and to minimize cross-reactivity. The major challenges in the development of the T-cell receptor-engineered T-cell therapy due to tumor microenvironment were also discussed here.
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Affiliation(s)
- Jianxiang Zhang
- The High School Affiliated to Renmin University, Beijing, People’s Republic of China
| | - Lingyu Wang
- Department of Biology, Duke University, Durham, NC, USA
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17
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Goyvaerts C, Breckpot K. The Journey of in vivo Virus Engineered Dendritic Cells From Bench to Bedside: A Bumpy Road. Front Immunol 2018; 9:2052. [PMID: 30254636 PMCID: PMC6141723 DOI: 10.3389/fimmu.2018.02052] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 08/20/2018] [Indexed: 12/13/2022] Open
Abstract
Dendritic cells (DCs) are recognized as highly potent antigen-presenting cells that are able to stimulate cytotoxic T lymphocyte (CTL) responses with antitumor activity. Consequently, DCs have been explored as cellular vaccines in cancer immunotherapy. To that end, DCs are modified with tumor antigens to enable presentation of antigen-derived peptides to CTLs. In this review we discuss the use of viral vectors for in situ modification of DCs, focusing on their clinical applications as anticancer vaccines. Among the viral vectors discussed are those derived from viruses belonging to the families of the Poxviridae, Adenoviridae, Retroviridae, Togaviridae, Paramyxoviridae, and Rhabdoviridae. We will further shed light on how the combination of viral vector-based vaccination with T-cell supporting strategies will bring this strategy to the next level.
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18
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Malamas AS, Gameiro SR, Knudson KM, Hodge JW. Sublethal exposure to alpha radiation (223Ra dichloride) enhances various carcinomas' sensitivity to lysis by antigen-specific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation. Oncotarget 2018; 7:86937-86947. [PMID: 27893426 PMCID: PMC5341329 DOI: 10.18632/oncotarget.13520] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 11/07/2016] [Indexed: 11/25/2022] Open
Abstract
Radium-223 dichloride (Xofigo®; 223Ra) is an alpha-emitting radiopharmaceutical FDA-approved for the treatment of bone metastases in patients with advanced castration-resistant prostate cancer. It is also being examined clinically in patients with breast and lung carcinoma and patients with multiple myeloma. As with other forms of radiation, the aim of 223Ra is to reduce tumor burden by directly killing tumor cells. External beam (photon) and proton radiation have been shown to augment tumor sensitivity to antigen-specific CD8+ cytotoxic T lymphocytes (CTLs). However, little is known about whether treatment with 223Ra can also induce such immunogenic modulation in tumor cells that survive irradiation. We examined these effects in vitro by exposing human prostate, breast, and lung carcinoma cells to sublethal doses of 223Ra. 223Ra significantly enhanced T cell-mediated lysis of each tumor type by CD8+ CTLs specific for MUC-1, brachyury, and CEA tumor antigens. Immunofluorescence analysis revealed that the increase in CTL killing was accompanied by augmented protein expression of MHC-I and calreticulin in each tumor type, molecules that are essential for efficient antigen presentation. Enhanced tumor-cell lysis was facilitated by calreticulin surface translocation following 223Ra exposure. The phenotypic changes observed after treatment appear to be mediated by induction of the endoplasmic reticulum stress response pathway. By rendering tumor cells more susceptible to T cell-mediated lysis, 223Ra may potentially be effective in combination with various immunotherapies, particularly cancer vaccines that are designed to generate and expand patients’ endogenous antigen-specific T-cell populations against specific tumor antigens.
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Affiliation(s)
- Anthony S Malamas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sofia R Gameiro
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Karin M Knudson
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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19
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Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, Grenga I, Kim YS, Brechbiel MW, Gulley JL, Madan RA, Heery CR, Hodge JW, Newton R, Schlom J, Tsang KY. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget 2018; 7:37762-37772. [PMID: 27192116 PMCID: PMC5122347 DOI: 10.18632/oncotarget.9326] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 04/26/2016] [Indexed: 12/20/2022] Open
Abstract
Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-γ plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83+ conventional DCs, and a decrease in immature activated Tim3+ NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines.
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Affiliation(s)
- Caroline Jochems
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Massimo Fantini
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Romaine I Fernando
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anna R Kwilas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lauren M Lepone
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Italia Grenga
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Young-Seung Kim
- Radioimmune Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Martin W Brechbiel
- Radioimmune Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Christopher R Heery
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kwong Y Tsang
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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20
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Dillon PM, Petroni GR, Smolkin ME, Brenin DR, Chianese-Bullock KA, Smith KT, Olson WC, Fanous IS, Nail CJ, Brenin CM, Hall EH, Slingluff CL. A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer. J Immunother Cancer 2017; 5:92. [PMID: 29157306 PMCID: PMC5697108 DOI: 10.1186/s40425-017-0295-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 10/18/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial. METHODS A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, -A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8+ T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays. RESULTS Twelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8+ T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series. CONCLUSIONS Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination. TRIAL REGISTRATION ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://clinicaltrials.gov/show/NCT01532960.
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Affiliation(s)
| | | | | | | | | | - Kelly T Smith
- University of Virginia, Charlottesville, VA, 22908, USA
| | | | | | - Carmel J Nail
- University of Virginia, Charlottesville, VA, 22908, USA
| | | | - Emily H Hall
- University of Virginia, Charlottesville, VA, 22908, USA
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21
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Trenevska I, Li D, Banham AH. Therapeutic Antibodies against Intracellular Tumor Antigens. Front Immunol 2017; 8:1001. [PMID: 28868054 PMCID: PMC5563323 DOI: 10.3389/fimmu.2017.01001] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 08/04/2017] [Indexed: 01/12/2023] Open
Abstract
Monoclonal antibodies are among the most clinically effective drugs used to treat cancer. However, their target repertoire is limited as there are relatively few tumor-specific or tumor-associated cell surface or soluble antigens. Intracellular molecules represent nearly half of the human proteome and provide an untapped reservoir of potential therapeutic targets. Antibodies have been developed to target externalized antigens, have also been engineered to enter into cells or may be expressed intracellularly with the aim of binding intracellular antigens. Furthermore, intracellular proteins can be degraded by the proteasome into short, commonly 8-10 amino acid long, peptides that are presented on the cell surface in the context of major histocompatibility complex class I (MHC-I) molecules. These tumor-associated peptide-MHC-I complexes can then be targeted by antibodies known as T-cell receptor mimic (TCRm) or T-cell receptor (TCR)-like antibodies, which recognize epitopes comprising both the peptide and the MHC-I molecule, similar to the recognition of such complexes by the TCR on T cells. Advances in the production of TCRm antibodies have enabled the generation of multiple TCRm antibodies, which have been tested in vitro and in vivo, expanding our understanding of their mechanisms of action and the importance of target epitope selection and expression. This review will summarize multiple approaches to targeting intracellular antigens with therapeutic antibodies, in particular describing the production and characterization of TCRm antibodies, the factors influencing their target identification, their advantages and disadvantages in the context of TCR therapies, and the potential to advance TCRm-based therapies into the clinic.
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Affiliation(s)
- Iva Trenevska
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Demin Li
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Alison H Banham
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
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22
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Tsang KY, Fantini M, Fernando RI, Palena C, David JM, Hodge JW, Gabitzsch ES, Jones FR, Schlom J. Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7. Vaccine 2017; 35:2605-2611. [PMID: 28389098 DOI: 10.1016/j.vaccine.2017.03.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/07/2017] [Indexed: 12/31/2022]
Abstract
Human papillomavirus (HPV) is associated with the etiology of cervical carcinoma, head and neck squamous cell carcinoma, and several other cancer types. Vaccines directed against HPV virus-like particles and coat proteins have been extremely successful in the prevention of cervical cancer through the activation of host HPV-specific antibody responses; however, HPV-associated cancers remain a major public health problem. The development of a therapeutic vaccine will require the generation of T-cell responses directed against early HPV proteins (E6/E7) expressed in HPV-infected tumor cells. Clinical studies using various vaccine platforms have demonstrated that both HPV-specific human T cells can be generated and patient benefit can be achieved. However, no HPV therapeutic vaccine has been approved by the Food and Drug Administration to date. One method of enhancing the potential efficacy of a therapeutic vaccine is the generation of agonist epitopes. We report the first description of enhancer cytotoxic T lymphocyte agonist epitopes for HPV E6 and E7. While the in silico algorithm revealed six epitopes with potentially improved binding to human leukocyte antigen-A2 allele (HLA-A2)-Class I, 5/6 demonstrated enhanced binding to HLA-Class I in cell-based assays and only 3/6 had a greater ability to activate HPV-specific T cells which could lyse tumor cells expressing native HPV, compared to their native epitope counterparts. These agonist epitopes have potential for use in a range of HPV therapeutic vaccine platforms and for use in HPV-specific adoptive T- or natural killer-cell platforms.
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Affiliation(s)
- Kwong Y Tsang
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | - Massimo Fantini
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | - Romaine I Fernando
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | - Claudia Palena
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | - Justin M David
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | | | - Frank R Jones
- Etubics Corporation, 41 West Harrison Street, Suite 100, Seattle, WA 98119, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
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23
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Gameiro SR, Malamas AS, Tsang KY, Ferrone S, Hodge JW. Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells. Oncotarget 2016; 7:7390-402. [PMID: 26862729 PMCID: PMC4884926 DOI: 10.18632/oncotarget.7180] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 01/23/2016] [Indexed: 12/22/2022] Open
Abstract
The clinical promise of cancer immunotherapy relies on the premise that the immune system can recognize and eliminate tumor cells identified as non-self. However, tumors can evade host immune surveillance through multiple mechanisms, including epigenetic silencing of genes involved in antigen processing and immune recognition. Hence, there is an unmet clinical need to develop effective therapeutic strategies that can restore tumor immune recognition when combined with immunotherapy, such as immune checkpoint blockade and therapeutic cancer vaccines. We sought to examine the potential of clinically relevant exposure of prostate and breast human carcinoma cells to histone deacetylase (HDAC) inhibitors to reverse tumor immune escape to T-cell mediated lysis. Here we demonstrate that prostate (LNCAP) and breast (MDA-MB-231) carcinoma cells are more sensitive to T-cell mediated lysis in vitro after clinically relevant exposure to epigenetic therapy with either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat. This pattern of immunogenic modulation was observed against a broad range of tumor-associated antigens, such as CEA, MUC1, PSA, and brachyury, and associated with augmented expression of multiple proteins involved in antigen processing and tumor immune recognition. Genetic and pharmacological inhibition studies identified HDAC1 as a key determinant in the reversal of carcinoma immune escape. Further, our findings suggest that the observed reversal of tumor immune evasion is driven by a response to cellular stress through activation of the unfolded protein response. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines.
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Affiliation(s)
- Sofia R Gameiro
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Anthony S Malamas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kwong Y Tsang
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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24
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McCann KJ, Mander A, Cazaly A, Chudley L, Stasakova J, Thirdborough S, King A, Lloyd-Evans P, Buxton E, Edwards C, Halford S, Bateman A, O'Callaghan A, Clive S, Anthoney A, Jodrell DI, Weinschenk T, Simon P, Sahin U, Thomas GJ, Stevenson FK, Ottensmeier CH. Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunologic and Clinical Outcomes. Clin Cancer Res 2016; 22:4827-4836. [PMID: 27091407 PMCID: PMC5330406 DOI: 10.1158/1078-0432.ccr-15-2507] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 03/29/2016] [Indexed: 12/22/2022]
Abstract
PURPOSE We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201-binding peptide CAP-1 from carcinoembryonic antigen (CEA605-613) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin. EXPERIMENTAL DESIGN Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (arm-I) and 12 patients without radiological evidence of disease (arm-II). Six intramuscular vaccinations of naked DNA (1 mg/dose) were administered up to week 12. Clinical and immunologic follow-up was up to week 64 or clinical/radiological disease. RESULTS DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared with 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8+ T cells, respectively. CAP-1-specific T cells were only detectable in the blood postvaccination but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (P < 0.001) and improved global immunologic responses [anti-DOM responses of greater magnitude (P < 0.001), frequency (P = 0.004), and duration] compared with patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR = 0.14, P = 0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass spectrometry, offering a mechanistic explanation for diarrhea through CD8+ T-cell attack. CONCLUSIONS Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody. Clin Cancer Res; 22(19); 4827-36. ©2016 AACR.
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Affiliation(s)
- Katy J McCann
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Ann Mander
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Angelica Cazaly
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Lindsey Chudley
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Jana Stasakova
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Stephen Thirdborough
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Andrew King
- University Hospital Southampton NHS Trust, Southampton, UK
| | - Paul Lloyd-Evans
- NHS Blood and Transplant, Clinical Biotechnology Centre, University of Bristol, Bristol, UK
| | - Emily Buxton
- Cancer Research UK Centre for Drug Development, London, UK
| | - Ceri Edwards
- Cancer Research UK Centre for Drug Development, London, UK
| | - Sarah Halford
- Cancer Research UK Centre for Drug Development, London, UK
| | - Andrew Bateman
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
- University Hospital Southampton NHS Trust, Southampton, UK
| | | | | | | | - Duncan I Jodrell
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
| | | | - Petra Simon
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
- BioNTech Cell & Gene Therapies GmbH, Mainz, Germany
| | - Ugur Sahin
- TRON gGmbH, Translational Oncology at the University Medical Center, Johannes Gutenberg-University, Mainz, Germany
| | - Gareth J Thomas
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
- University Hospital Southampton NHS Trust, Southampton, UK
| | - Freda K Stevenson
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Christian H Ottensmeier
- Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK
- University Hospital Southampton NHS Trust, Southampton, UK
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25
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A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-α-2b in patients with CEA-expressing carcinomas. Cancer Immunol Immunother 2016; 65:1353-1364. [PMID: 27581603 DOI: 10.1007/s00262-016-1893-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 08/25/2016] [Indexed: 12/22/2022]
Abstract
Prime-boost vaccination with recombinant (r) vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM infect antigen-presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with GM-CSF and interferon alpha (IFN-α) would have efficacy in CEA-expressing cancers. Patients with CEA-expressing cancers received the rV-CEA(6D)-TRICOM vaccine subcutaneously (s.c.) on day 1 followed by GM-CSF s.c. to the injection site on days 1-4. In Cycle 1, patients received thrice weekly s.c. injections of IFN-α-2b the week after rV-CEA(6D)-TRICOM. In Cycles 2-4, patients received thrice weekly s.c. injections of IFN-α-2b the same week that rF-CEA(6D)-TRICOM was given. The first cohort received no IFN followed by dose escalation of IFN-α in subsequent cohorts. Thirty-three patients were accrued (mean 59.8 years). Grade 3 toxicities included fatigue and hyperglycemia. Grade 4-5 adverse events (unrelated to treatment) were confusion (1), elevated aspartate transaminase (AST)/alanine transaminase (ALT) (1), and sudden death (1). No patients had a partial response, and eight patients exhibited stable disease of ≥3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy (p = 0.006 post 1-2 cycles, p = 0.003 post 3 cycles, p = 0.03 post 4-7 cycles) and 42 % of patients assayed developed CEA-specific T cell responses. Pre-treatment levels of myeloid-derived suppressor cells correlated with overall survival (p = 0.04). Administration of IFN-α led to significantly increased OS (p = 0.02) compared to vaccine alone. While the vaccine regimen produced no clinical responses, IFN-α administration was associated with improved survival.
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Combined expression of miR-34a and Smac mediated by oncolytic vaccinia virus synergistically promote anti-tumor effects in Multiple Myeloma. Sci Rep 2016; 6:32174. [PMID: 27552933 PMCID: PMC5001249 DOI: 10.1038/srep32174] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 08/03/2016] [Indexed: 02/07/2023] Open
Abstract
Despite great progress made in the treatment of multiple myeloma (MM), it is still incurable. Promising phase II clinical results have been reported recently for oncolytic vaccinia virus (OVV) clinic therapeutics. One reason for this has focused on the critical therapeutic importance of the immune response raised by these viruses. However, few studies have performed their applications as an optimal delivery system for therapeutic gene, especially miRNA in MM. In this study, we constructed two novel OVVs (TK deletion) that express anti-tumor genes, miR-34a and Smac, respectively, in MM cell lines and xenograft model. The results demonstrated that the novel OVV can effectively infect MM cell lines, and forcefully enhance the exogenous gene (miR-34a or Smac) expression. Furthermore, utilization of VV-miR-34a combined with VV-Smac synergistically inhibited tumor growth and induced apoptosis in vitro and in vivo. The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac-induced cell apoptosis. Our study is the first to utilize OVV as the vector for miR-34a or Smac expression to treat MM, and lays the groundwork for future clinical therapy for MM.
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Gabitzsch ES, Tsang KY, Palena C, David JM, Fantini M, Kwilas A, Rice AE, Latchman Y, Hodge JW, Gulley JL, Madan RA, Heery CR, Balint JP, Jones FR, Schlom J. The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic. Oncotarget 2016; 6:31344-59. [PMID: 26374823 PMCID: PMC4741610 DOI: 10.18632/oncotarget.5181] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/24/2015] [Indexed: 12/11/2022] Open
Abstract
Phenotypic heterogeneity of human carcinoma lesions, including heterogeneity in expression of tumor-associated antigens (TAAs), is a well-established phenomenon. Carcinoembryonic antigen (CEA), MUC1, and brachyury are diverse TAAs, each of which is expressed on a wide range of human tumors. We have previously reported on a novel adenovirus serotype 5 (Ad5) vector gene delivery platform (Ad5 [E1-, E2b-]) in which regions of the early 1 (E1), early 2 (E2b), and early 3 (E3) genes have been deleted. The unique deletions in this platform result in a dramatic decrease in late gene expression, leading to a marked reduction in host immune response to the vector. Ad5 [E1-, E2b-]-CEA vaccine (ETBX-011) has been employed in clinical studies as an active vaccine to induce immune responses to CEA in metastatic colorectal cancer patients. We report here the development of novel recombinant Ad5 [E1-, E2b-]-brachyury and-MUC1 vaccine constructs, each capable of activating antigen-specific human T cells in vitro and inducing antigen-specific CD4+ and CD8+ T cells in vaccinated mice. We also describe the use of a combination of the three vaccines (designated Tri-Ad5) of Ad5 [E1-, E2b-]-CEA, Ad5 [E1-, E2b-]-brachyury and Ad5 [E1-, E2b-]-MUC1, and demonstrate that there is minimal to no “antigenic competition” in in vitro studies of human dendritic cells, or in murine vaccination studies. The studies reported herein support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies.
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Affiliation(s)
| | - Kwong Yok Tsang
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Claudia Palena
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Justin M David
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Massimo Fantini
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anna Kwilas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | | | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Christopher R Heery
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | | | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Gameiro SR, Malamas AS, Bernstein MB, Tsang KY, Vassantachart A, Sahoo N, Tailor R, Pidikiti R, Guha CP, Hahn SM, Krishnan S, Hodge JW. Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing. Int J Radiat Oncol Biol Phys 2016; 95:120-130. [PMID: 27084634 PMCID: PMC4834148 DOI: 10.1016/j.ijrobp.2016.02.022] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 01/06/2016] [Accepted: 02/05/2016] [Indexed: 01/09/2023]
Abstract
PURPOSE To provide the foundation for combining immunotherapy to induce tumor antigen-specific T cells with proton radiation therapy to exploit the activity of those T cells. METHODS AND MATERIALS Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. RESULTS These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. CONCLUSIONS These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.
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Affiliation(s)
- Sofia R Gameiro
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Anthony S Malamas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Michael B Bernstein
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - Kwong Y Tsang
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - April Vassantachart
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - Narayan Sahoo
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - Ramesh Tailor
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - Rajesh Pidikiti
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - Chandan P Guha
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, New York
| | - Stephen M Hahn
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - Sunil Krishnan
- Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Heery CR, Ibrahim NK, Arlen PM, Mohebtash M, Murray JL, Koenig K, Madan RA, McMahon S, Marté JL, Steinberg SM, Donahue RN, Grenga I, Jochems C, Farsaci B, Folio LR, Schlom J, Gulley JL. Docetaxel Alone or in Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Oncol 2016; 1:1087-95. [PMID: 26291768 DOI: 10.1001/jamaoncol.2015.2736] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
IMPORTANCE Previous phase 1 and 2 trials of PANVAC, a poxviral-based cancer vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell-mediated killing. OBJECTIVE The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast cancer compared with docetaxel treatment alone. DESIGN, SETTING, AND PARTICIPANTS Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P≤.10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. RESULTS Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema (P=.02, likely related to greater median number of docetaxel cycles) and injection-site reactions (P<.001). In the final data analysis, median PFS was 7.9 months in arm A vs 3.9 months in arm B (hazard ratio, 0.65 [95% CI, 0.34-1.14]; P=.09). CONCLUSIONS AND RELEVANCE The results suggest that the combination of PANVAC with docetaxel in metastatic breast cancer may provide a clinical benefit. This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179309.
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Affiliation(s)
- Christopher R Heery
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Nuhad K Ibrahim
- Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Philip M Arlen
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Mahsa Mohebtash
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - James L Murray
- Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Kimberly Koenig
- Division of Cancer Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sheri McMahon
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jennifer L Marté
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Italia Grenga
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Caroline Jochems
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Benedetto Farsaci
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Les R Folio
- Radiology and Imaging Services, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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Kumari A, Garnett-Benson C. Effector function of CTLs is increased by irradiated colorectal tumor cells that modulate OX-40L and 4-1BBL and is reversed following dual blockade. BMC Res Notes 2016; 9:92. [PMID: 26872462 PMCID: PMC4752774 DOI: 10.1186/s13104-016-1914-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 02/03/2016] [Indexed: 01/10/2023] Open
Abstract
Background Sub-lethal doses of ionizing radiation (IR) can alter the phenotype of target tissue by modulating genes that influence effector T cell activity. Previous studies indicate that cancer cells respond to radiation by up-regulating surface expression of death receptors, cell adhesion molecules and tumor-associated antigens (TAA). However, there is limited information available regarding how T cells themselves are altered following these interactions with irradiated tumor cells. Methods Here, several human colorectal tumor cell lines were exposed to radiation (0–10 Gy) in vitro and changes in the expression of molecules costimulatory to effector T cells (4-1BBL, OX-40L, CD70, ICOSL) were examined by flow cytometry. T cell effector function was assessed to determine if changes in these proteins were directly related to the changes in T cell function. Results We found OX-40L and 4-1BBL to be the most consistently upregulated proteins on the surface of colorectal tumor cells post-IR while ICOSL and CD70 remained largely unaltered. Expression of these gene products correlated with enhanced killing of irradiated human colorectal tumor cells by TAA-specific T-cells. Importantly, blocking of both OX-40L and 4-1BBL reversed radiation-enhanced T-cell killing of human tumor targets as well as T-cell survival and activation. Conclusions Overall, results of this study suggest that, beyond simply rendering tumor cells more sensitive to immune attack, radiation can be used to specifically modulate expression of genes that directly stimulate effector T cell activity.
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Affiliation(s)
- Anita Kumari
- Department of Biology, Georgia State University, 161 Jesse Hill Jr. Dr, Atlanta, GA, 30303, USA.
| | - Charlie Garnett-Benson
- Department of Biology, Georgia State University, 161 Jesse Hill Jr. Dr, Atlanta, GA, 30303, USA.
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Gulbake A, Jain A, Jain A, Jain A, Jain SK. Insight to drug delivery aspects for colorectal cancer. World J Gastroenterol 2016; 22:582-599. [PMID: 26811609 PMCID: PMC4716061 DOI: 10.3748/wjg.v22.i2.582] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/29/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide in human beings. Surgery, chemotherapy, radiotherapy and targeted therapies are the conventional four approaches which are currently used for the treatment of CRC. The site specific delivery of chemotherapeutics to their site of action would increase effectiveness with reducing side effects. Targeted oral drug delivery systems based on polysaccharides are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific drug delivery to colon increases its concentration at the target site, and thus requires a lower dose and hence abridged side effects. Some novel therapies are also briefly discussed in article such as receptor (epidermal growth factor receptor, folate receptor, wheat germ agglutinin, VEGF receptor, hyaluronic acid receptor) based targeting therapy; colon targeted proapoptotic anticancer drug delivery system, gene therapy. Even though good treatment options are available for CRC, the ultimate therapeutic approach is to avert the incidence of CRC. It was also found that CRCs could be prevented by diet and nutrition such as calcium, vitamin D, curcumin, quercetin and fish oil supplements. Immunotherapy and vaccination are used nowadays which are showing better results against CRC.
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Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack. Int J Mol Sci 2015; 16:30405-21. [PMID: 26703577 PMCID: PMC4691179 DOI: 10.3390/ijms161226238] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 12/08/2015] [Accepted: 12/11/2015] [Indexed: 01/05/2023] Open
Abstract
Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity.
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Grenga I, Kwilas AR, Donahue RN, Farsaci B, Hodge JW. Inhibition of the angiopoietin/Tie2 axis induces immunogenic modulation, which sensitizes human tumor cells to immune attack. J Immunother Cancer 2015; 3:52. [PMID: 26579226 PMCID: PMC4647578 DOI: 10.1186/s40425-015-0096-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 10/21/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The angiopoietin/Tie2 pathway is an attractive target for cancer therapy due to its well-known role in regulating angiogenesis. Trebananib, a recombinant peptide-Fc fusion protein, or peptibody, that binds to angiopoietin-1 (Ang1) and Ang2 to block their interaction with the Tie2 receptor, is under active clinical investigation. We investigated whether suppressing the angiopoietin/Tie2 pathway, using the preclinical version of Trebananib (mL4-3 and L1-7(N)), could increase the sensitivity of human tumor cells to immune-mediated lysis through immunogenic modulation, which would make Trebananib a promising candidate for combination with immunotherapy. METHODS We assessed human carcinoma cells for expression and activation of Ang1 and Ang2 and their receptor tyrosine kinase Tie2. In vitro, we exposed tumor cell lines expressing Tie2 to the peptibodies mL4-3 and L1-7(N), which inhibit the binding of Ang1 and Ang2 to Tie2, and assessed the cells for changes in viability, proliferation, surface phenotype, and sensitivity to attack by antigen-specific cytotoxic T lymphocytes (CTLs). RESULTS Suppression of the angiopoietin/Tie2 pathway using mL4-3 and L1-7(N) had no effect on the proliferation or viability of tumor cells. However, these inhibitors markedly altered tumor cell phenotype, rendering tumor cells significantly more sensitive to antigen-specific CTL killing. ICAM-1 was shown to be mechanistically involved in these inhibitors' ability to sensitize tumor cells to immune-mediated attack by functional blocking studies. CONCLUSION Our findings provide a rationale for the combination of agents targeting the angiopoietin/Tie2 pathway with cancer immunotherapies.
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Affiliation(s)
- Italia Grenga
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Center Drive, Room 8B13 MSC 1750, Bethesda, MD 20892 USA
| | - Anna R Kwilas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Center Drive, Room 8B13 MSC 1750, Bethesda, MD 20892 USA
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Center Drive, Room 8B13 MSC 1750, Bethesda, MD 20892 USA
| | - Benedetto Farsaci
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Center Drive, Room 8B13 MSC 1750, Bethesda, MD 20892 USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Center Drive, Room 8B13 MSC 1750, Bethesda, MD 20892 USA
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Ardiani A, Gameiro SR, Kwilas AR, Donahue RN, Hodge JW. Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway. Oncotarget 2015; 5:9335-48. [PMID: 25344864 PMCID: PMC4253438 DOI: 10.18632/oncotarget.2429] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT.
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Affiliation(s)
- Andressa Ardiani
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sofia R Gameiro
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anna R Kwilas
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Dubrovsky L, Dao T, Gejman RS, Brea EJ, Chang AY, Oh CY, Casey E, Pankov D, Scheinberg DA. T cell receptor mimic antibodies for cancer therapy. Oncoimmunology 2015; 5:e1049803. [PMID: 26942058 DOI: 10.1080/2162402x.2015.1049803] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 05/06/2015] [Indexed: 01/01/2023] Open
Abstract
The major hurdle to the creation of cancer-specific monoclonal antibodies (mAb) exhibiting limited cross-reactivity with healthy human cells is the paucity of known tumor-specific or mutated protein epitopes expressed on the cancer cell surface. Mutated and overexpressed oncoproteins are typically cytoplasmic or nuclear. Cells can present peptides from these distinguishing proteins on their cell surface in the context of human leukocyte antigen (HLA). T cell receptor mimic (TCRm) mAb can be discovered that react specifically to these complexes, allowing for selective targeting of cancer cells. The state-of-the-art for TCRm and the challenges and opportunities are discussed. Several such TCRm are moving toward clinical trials now.
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Affiliation(s)
| | - Tao Dao
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Ron S Gejman
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Elliott J Brea
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Aaron Y Chang
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Claire Y Oh
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Emily Casey
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Dmitry Pankov
- Memorial Sloan Kettering Cancer Center ; New York, NY USA
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Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 2015; 5:403-16. [PMID: 24480782 PMCID: PMC3964216 DOI: 10.18632/oncotarget.1719] [Citation(s) in RCA: 292] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response. This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone.
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Affiliation(s)
- Sofia R Gameiro
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Hartley ML, Bade NA, Prins PA, Ampie L, Marshall JL. Pancreatic cancer, treatment options, and GI-4000. Hum Vaccin Immunother 2015; 11:931-7. [PMID: 25933185 PMCID: PMC4514241 DOI: 10.1080/21645515.2015.1011017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 11/10/2014] [Accepted: 11/14/2014] [Indexed: 12/13/2022] Open
Abstract
Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year, which is reduced to 6% after 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors-RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials.
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Affiliation(s)
- Marion L Hartley
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - Najeebah A Bade
- The Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - Petra A Prins
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - Leonel Ampie
- The Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - John L Marshall
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
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Peptide-Based Vaccination and Induction of CD8+ T-Cell Responses Against Tumor Antigens in Breast Cancer. BioDrugs 2014; 29:15-30. [DOI: 10.1007/s40259-014-0114-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Choi M, Thakur A. Identifying Appropriate Colorectal Cancer-Associated Antigens for the Clinical Trials. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0256-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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A Monoclonal Antibody Against Neem Leaf Glycoprotein Recognizes Carcinoembryonic Antigen (CEA) and Restricts CEA Expressing Tumor Growth. J Immunother 2014; 37:394-406. [DOI: 10.1097/cji.0000000000000050] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Tucker JA, Jochems C, Boyerinas B, Fallon J, Greiner JW, Palena C, Rodell TC, Schlom J, Tsang KY. Identification and characterization of a cytotoxic T-lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis. Cancer Immunol Immunother 2014; 63:1307-17. [PMID: 25186612 DOI: 10.1007/s00262-014-1603-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 08/12/2014] [Indexed: 12/31/2022]
Abstract
The transcription factor brachyury is a major driver of epithelial to mesenchymal transition in human carcinoma cells. It is overexpressed in several human tumor types versus normal adult tissues, except for testes and thyroid. Overexpression is associated with drug resistance and poor prognosis. Previous studies identified a brachyury HLA-A2 cytotoxic T-lymphocyte epitope. The studies reported here describe an enhancer epitope of brachyury. Compared to the native epitope, the agonist epitope: (a) has enhanced binding to MHC class I, (b) increased the IFN-γ production from brachyury-specific T cells, (c) generated brachyury-specific T cells with greater levels of perforin and increased proliferation, (d) generated T cells more proficient at lysing human carcinoma cells endogenously expressing the native epitope, and (e) achieved greater brachyury-specific T-cell responses in vivo in HLA-A2 transgenic mice. These studies also report the generation of a heat-killed recombinant Saccharomyces cerevisiae (yeast) vector expressing the full-length brachyury gene encoding the agonist epitope. Compared to yeast-brachyury (native) devoid of the agonist epitope, the yeast-brachyury (agonist) enhanced the activation of brachyury-specific T cells, which efficiently lysed human carcinoma cells. In addition to providing the rationale for the recombinant yeast-brachyury (agonist) as a potential vaccine in cancer therapy, these studies also provide the rationale for the use of the agonist in (a) dendritic cell (DC) vaccines, (b) adjuvant or liposomal vaccines, (c) recombinant viral and/or bacterial vaccines, (d) protein/polypeptide vaccines, (e) activation of T cells ex vivo in adoptive therapy protocols, and (f) generation of genetically engineered targeted T cells.
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Affiliation(s)
- Jo A Tucker
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, MSC 1750, Bethesda, MD, 20892, USA
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A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines. Vaccine 2014; 32:3223-31. [PMID: 24731809 DOI: 10.1016/j.vaccine.2014.04.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/26/2014] [Accepted: 04/01/2014] [Indexed: 01/03/2023]
Abstract
Recent studies have suggested that pan inhibitors of dipeptidyl peptidase-4 activity and/or structure homologs (DASH), including ARI-4175, can mediate tumor regression by immune-mediated mechanisms. This study assessed the potential of combining ARI-4175 with cancer vaccines. We evaluated ARI-4175's effect on immunogenic modulation, ability to sensitize tumor cells to antigen-specific CTL killing, effect on immune-cell subsets and function, and antitumor activity in 2 tumor models, both as a monotherapy and in combination with a recombinant viral or dendritic cell (DC)-based tumor-cell vaccine. ARI-4175's effects on the growth, surface phenotype, and antigen-specific CTL-mediated lysis of murine and human carcinoma cell lines were assessed in vitro. In vivo, C57BL-6 mice were treated orally with ARI-4175, after which splenocytes were assessed by flow cytometry and functional assays. Antitumor studies were performed in murine models of colon carcinoma (MC38-CEA(+) in CEA-transgenic C57BL-6 mice) and rhabdomyosarcoma (M3-9-M in C57BL-6 mice). Mice received oral ARI-4175 alone or in combination with a vaccine consisting of recombinant vaccinia/fowlpox CEA-TRICOM (colon model) or a DC-based tumor-cell vaccine (rhabdomyosarcoma model). Exposure to ARI-4175 had no effect on the proliferation or viability of carcinoma cells in vitro; however, it did alter tumor phenotype, making murine and human tumor cells more sensitive to antigen-specific CTL killing. Assessment of immune-cell subsets and function indicated that ARI-4175 increased levels of natural killer cells and DCs. Detrimental immune effects, including reduced T effector cells and increased immunosuppressive cells (Tregs, MDSCs), were normalized when treatment stopped, suggesting that scheduling is critical when combining this agent with vaccine. As a monotherapy, ARI-4175 had potent antitumor activity in both tumor models, and had even greater effects when combined with a vaccine (either DC-based or poxviral vector based). These findings provide the rationale for the combined use of cancer immunotherapy with DASH enzyme inhibitors such as ARI-4175.
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Bernstein MB, Garnett CT, Zhang H, Velcich A, Wattenberg MM, Gameiro SR, Kalnicki S, Hodge JW, Guha C. Radiation-induced modulation of costimulatory and coinhibitory T-cell signaling molecules on human prostate carcinoma cells promotes productive antitumor immune interactions. Cancer Biother Radiopharm 2014; 29:153-61. [PMID: 24693958 DOI: 10.1089/cbr.2013.1578] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We sought to determine if single-dose external beam radiation therapy (EBRT) could modulate the expression signature of T-cell costimulatory and coinhibitory molecules in human prostate cancer (PCa) cell lines in vitro. We investigated the functional impact of irradiated PCa cells with a modulated costimulatory profile on responder T-cell activity. We used three PCa cell lines (DU145, PC3, and LNCaP) and two epithelial cell lines from noncancerous prostate and lung tissue. After 72 hours of EBRT, surface expression of four immunostimulatory molecules (CD70, CD275/ICOSL, CD134L/OX40L, and CD137L/41BBL) and two immunosuppressive markers (CTLA-4/CD152 and PD-L1/CD274) were evaluated by flow cytometry. We evaluated the impact of several radiation doses and the longevity of modulated expression. We examined the functional impact of radiation-induced modulation of cancer cells by cytotoxic T cells (CTL) cytotoxicity and ELISPOT assay for interferon-gamma (IFN-γ) production. Last, we evaluated whether IFN-γ-induced PD-L1 expression could be reversed by EBRT. After 10 Gy EBRT, expression of OX40L and 41BBL increased in all three PCa cell lines; expression of CD70 and ICOSL increased in PC3 cells. Conversely, a decrease in PD-L1 expression in DU145 and PC3 cells was detectable up to 144 hours after EBRT. No PD-L1 was detected in LNCaP. Epithelial cells from normal prostate were not modulated by radiation. CTL cytolytic activity and IFN-γ production were enhanced by interaction with irradiated PCa cells. Finally, EBRT failed to prevent IFN-γ-induced upregulation of PD-L1. We demonstrate that a single dose of EBRT increased surface expression of costimulatory molecules and decreased the expression of coinhibitory molecules in human PCa cell lines. Changes in irradiated tumor cells led to functional enhancement of T-cell activity, despite EBRT failing to reduce IFN-γ-induced expression of PD-L1. These data suggest that combining radiotherapy with T-cell stimulating immunotherapy may be an attractive strategy for cancer treatment.
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Affiliation(s)
- Michael B Bernstein
- 1 Department of Radiation Oncology, Montefiore Medical Center , Albert Einstein College of Medicine, Bronx, New York
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Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res 2014; 119:421-75. [PMID: 23870514 DOI: 10.1016/b978-0-12-407190-2.00007-1] [Citation(s) in RCA: 373] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Therapeutic vaccines represent a viable option for active immunotherapy of cancers that aim to treat late stage disease by using a patient's own immune system. The promising results from clinical trials recently led to the approval of the first therapeutic cancer vaccine by the U.S. Food and Drug Administration. This major breakthrough not only provides a new treatment modality for cancer management but also paves the way for rationally designing and optimizing future vaccines with improved anticancer efficacy. Numerous vaccine strategies are currently being evaluated both preclinically and clinically. This review discusses therapeutic cancer vaccines from diverse platforms or targets as well as the preclinical and clinical studies employing these therapeutic vaccines. We also consider tumor-induced immune suppression that hinders the potency of therapeutic vaccines, and potential strategies to counteract these mechanisms for generating more robust and durable antitumor immune responses.
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Affiliation(s)
- Chunqing Guo
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 2014; 14:135-46. [PMID: 24457417 DOI: 10.1038/nrc3670] [Citation(s) in RCA: 839] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.
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Affiliation(s)
- Pierre G Coulie
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] WELBIO (Walloon Excellence in Lifesciences and Biotechnology), B-1200 Brussels, Belgium
| | - Benoît J Van den Eynde
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. [3] WELBIO (Walloon Excellence in Lifesciences and Biotechnology), B-1200 Brussels, Belgium
| | - Pierre van der Bruggen
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium. [3] WELBIO (Walloon Excellence in Lifesciences and Biotechnology), B-1200 Brussels, Belgium
| | - Thierry Boon
- 1] de Duve Institute and the Université catholique de Louvain, B-1200 Brussels, Belgium. [2] Ludwig Institute for Cancer Research, B-1200 Brussels, Belgium
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A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Ann Surg 2014; 258:879-86. [PMID: 23657083 DOI: 10.1097/sla.0b013e318292919e] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142).
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Atreya I, Neurath MF. Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies. Expert Rev Anticancer Ther 2014; 8:561-72. [DOI: 10.1586/14737140.8.4.561] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Curigliano G, Spitaleri G, Dettori M, Locatelli M, Scarano E, Goldhirsch A. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Rev Anticancer Ther 2014; 7:1225-41. [PMID: 17892423 DOI: 10.1586/14737140.7.9.1225] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cancer vaccine-based immunotherapy should potentiate immunosurveillance function, preventing and protecting against growing tumors. Tumor cells usually activate the immune system, including T lymphocytes and natural killer cells, which are able to eliminate the transformed cells. Immunosubversion mechanisms related to tumor cells antigenic immunoediting induces mechanisms of tolerance and immunoescape. This condition impairs not only host-generated immunosurveillance, but also attempts to harness the immune response for therapeutic purposes. Most trials evaluating breast cancer vaccines have been carried out in patients in the metastatic and adjuvant setting. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. We summarize the differential approaches, protein-based and cell-based vaccines, focusing on vaccines targeting HER2/neu protein. Another focus of the review is to provide the reader with future challenges in the field, taking into account both the immunological and clinical aspects to better target the goal.
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Affiliation(s)
- Giuseppe Curigliano
- European Institute of Oncology, Department of Medicine, Division of Medical Oncology, Via Ripamonti 435, 20141 Milan, Italy.
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Pavlenko M, Leder C, Pisa P. Plasmid DNA vaccines against cancer: cytotoxic T-lymphocyte induction against tumor antigens. Expert Rev Vaccines 2014; 4:315-27. [PMID: 16026247 DOI: 10.1586/14760584.4.3.315] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In recent years, a number of tumor vaccination strategies have been developed. Most of these rely on the identification of tumor antigens that can be recognized by the immune system. DNA vaccination represents one such approach for the induction of both humoral and cellular immune responses against tumor antigens. Studies in animal models have demonstrated the feasibility of utilizing DNA vaccination to elicit protective antitumor immune responses. However, most tumor antigens expressed by cancer cells in humans are weakly immunogenic, and therefore require the development of strategies to potentiate DNA vaccine efficacy in the clinical setting. This review focuses on recent advances in understanding of the immunology of DNA vaccines, as well as strategies used to increase DNA vaccine potency with respect to cytotoxic T-lymphocyte activity.
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Affiliation(s)
- Maxim Pavlenko
- Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm S-171 76, Sweden.
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Mittendorf EA, Alatrash G, Xiao H, Clifton GT, Murray JL, Peoples GE. Breast cancer vaccines: ongoing National Cancer Institute-registered clinical trials. Expert Rev Vaccines 2014; 10:755-74. [DOI: 10.1586/erv.11.59] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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