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1
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Tulsian K, Thakker D, Vyas VK. Overcoming chimeric antigen receptor-T (CAR-T) resistance with checkpoint inhibitors: Existing methods, challenges, clinical success, and future prospects : A comprehensive review. Int J Biol Macromol 2025; 306:141364. [PMID: 39988153 DOI: 10.1016/j.ijbiomac.2025.141364] [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: 08/09/2024] [Revised: 11/20/2024] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
Immune checkpoint blockade is, as of today, the most successful form of cancer immunotherapy, with more than 43 % of cancer patients in the US eligible to receive it; however, only up to 12.5 % of patients respond to it. Similarly, adoptive cell therapy using bioengineered chimeric antigen receptorT (CAR-T) cells and T-cell receptor (TCR) cells has provided excellent responses against liquid tumours, but both forms of immunotherapy have encountered challenges within a tumour microenvironment that is both lacking in tumour-specific T-cells and is strongly immunosuppressive toward externally administered CAR-T and TCR cells. This review focuses on understanding approved checkpoint blockade and adoptive cell therapy at both biological and clinical levels before delving into how and why their combination holds significant promise in overcoming their individual shortcomings. The advent of next-generation checkpoint inhibitors has further strengthened the immune checkpoint field, and a special section explores how these inhibitors can address existing hurdles in combining checkpoint blockade with adoptive cell therapy and homing in on our cancer target for long-term immunity.
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Affiliation(s)
- Kartik Tulsian
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India
| | - Dhinal Thakker
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India
| | - Vivek K Vyas
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India.
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2
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Zeng S, Jin N, Yu B, Ren Q, Yan Z, Fu S. Chimeric antigen receptor-T cells targeting epithelial cell adhesion molecule antigens are effective in the treatment of colorectal cancer. BMC Gastroenterol 2024; 24:249. [PMID: 39107717 PMCID: PMC11302356 DOI: 10.1186/s12876-024-03286-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/07/2024] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVE To construct chimeric antigen receptor (CAR)-T cells targeting epithelial cell adhesion molecule (EpCAM) antigen (anti-EpCAM-CAR-T). METHODS A third-generation CAR-T cell construct used a single-chain variable fragment derived from monoclonal antibody against human EpCAM. Peripheral blood mononuclear cells were extracted from volunteers. The proportion of cluster of differentiation 8 positive (CD8+) and CD4 + T cells was measured using flow cytometry. Western blot was used to detect the expression of EpCAM-CAR. The killing efficiency was detected using the MTT assay and transwell assay, and the secretion of killer cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) was detected using the ELISA. The inhibitory effect of EpCAM-CAR-T on colorectal cancer in vivo was detected using xenografts. RESULTS It was found that T cells expanded greatly, and the proportion of CD3+, CD8 + and CD4 + T cells was more than 60%. Furthermore, EpCAM-CAR-T cells had a higher tumour inhibition rate in the EpCAM expression positive group than in the negative group (P < 0.05). The secretion of killer cytokines TNF-α and IFN-γ in the EpCAM expression positive cell group was higher than that in the negative group (P < 0.05). In the experimental group treated with EpCAM-CAR-T cells, the survival rate of nude mice was higher (P < 0.05), and the tumour was smaller than that in the blank and control groups (P < 0.05). The secretion of serum killer cytokines TNF-α and IFN-γ in tumour-bearing nude mice in the experimental group treated with EpCAM-CAR-T cells was higher than that in the blank and control groups (P < 0.05). CONCLUSION This study successfully constructed EpCAM-CAR cells and found that they can target and recognise EpCAM-positive tumour cells, secrete killer cytokines TNF-α and IFN-γ and better inhibit the growth and metastasis of colorectal cancer in vitro and in vivo than unmodified T cells.
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Affiliation(s)
- Siheng Zeng
- Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 201700, China
- Birth Defects and Regenerative Medicine Laboratory, Department of Biochemistry & Molecular Biology, Biomedicine and Health Graduate Education Innovation Center, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, Shanxi, 030001, China
| | - Ning Jin
- Birth Defects and Regenerative Medicine Laboratory, Department of Biochemistry & Molecular Biology, Biomedicine and Health Graduate Education Innovation Center, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, Shanxi, 030001, China
| | - Baofeng Yu
- Birth Defects and Regenerative Medicine Laboratory, Department of Biochemistry & Molecular Biology, Biomedicine and Health Graduate Education Innovation Center, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, Shanxi, 030001, China
| | - Qing Ren
- Department of Gynecology, Hainan West Central Hospital, Danzhou, Hainan, 571700, China
| | - Zhiqiang Yan
- Department of Gynecology, Hainan West Central Hospital, Danzhou, Hainan, 571700, China
| | - Songtao Fu
- Birth Defects and Regenerative Medicine Laboratory, Department of Biochemistry & Molecular Biology, Biomedicine and Health Graduate Education Innovation Center, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, Shanxi, 030001, China.
- Biomedicine and Health Graduate Education Innovation Center, Taiyuan, Shanxi, 030001, China.
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3
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Chantarat N, Pe KCS, Suppipat K, Vimolmangkang S, Tawinwung S. Effects of Cannabidiol on the Functions of Chimeric Antigen Receptor T Cells in Hematologic Malignancies. Cannabis Cannabinoid Res 2024; 9:819-829. [PMID: 37878339 DOI: 10.1089/can.2023.0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2023] Open
Abstract
Introduction: CD19-chimeric antigen receptor (CAR) T cell therapy is a promising immunotherapy for cancer treatment that has shown remarkable clinical responses, leading to approval by the FDA for relapsed and refractory B cell hematological malignancy treatment. Cannabidiol (CBD) is a nonpsychoactive cannabinoid compound that has been utilized as a palliative treatment in cancer patients due to its immunosuppressive properties. Currently, studies on using CBD during immunotherapy have gained increasing attention. However, the possible interaction between CBD and CAR T cell therapy has not been studied. Therefore, in this study, we aimed to examine the direct effects of CBD on CD19-CAR T cell function against hematologic malignancies. Materials and Methods: The cytotoxic effect of CBD was determined by a cell proliferation reagent water-soluble tatrazolium salt (WST-1) assay. CAR T cells were generated by retroviral transduction and treated with CBD at a nontoxic dose. The effect of CBD on immune characteristics, including transgene expression, T cell subset, and memory phenotype, was analyzed by flow cytometry. Proliferation, apoptosis, and cell cycle distribution were analyzed with standard methods. The effect on cytotoxic function was evaluated using degranulation assays, and antitumor activity was evaluated using flow cytometry. Results: The half-maximum inhibitory concentration (IC50) of CBD on NALM6, Raji, and T cells ranged from 16 to 22 μM. The maximum nontoxic dose of CBD that maintained cell viability at ∼100% was 8 μM. For the generation of CD19-CAR T cells, primary T cells were activated and transduced with a retroviral vector encoding CD19-CAR. CBD did not alter the surface expression or immune characteristics, including the T cell subset and memory phenotype, of CD19-CAR T cells. However, CBD suppressed CD19-CAR T cell proliferation by inducing apoptosis, as evidenced by an increase in the proportion of cells in the Sub-G1 phase in cell cycle arrest. However, the antitumor activity and cytokine secretion of CD19-CAR T cells were not altered by exposure to CBD in this study. Conclusions: In this study, a nontoxic dose of CBD affected CD19-CAR T cell proliferation but not its immune characteristics or cytotoxic function.
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Affiliation(s)
- Natthida Chantarat
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Kristine Cate S Pe
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Koramit Suppipat
- Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Cellular Immunotherapy Research Unit, Chulalongkorn University, Bangkok, Thailand
- Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, Thailand
| | - Sornkanok Vimolmangkang
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Research Cluster for Cannabis and its Natural Substances, Chulalongkorn University, Bangkok, Thailand
| | - Supannikar Tawinwung
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Cellular Immunotherapy Research Unit, Chulalongkorn University, Bangkok, Thailand
- Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, Thailand
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4
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Perna F, Espinoza-Gutarra MR, Bombaci G, Farag SS, Schwartz JE. Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia. Cancer Treat Res 2022; 183:225-254. [PMID: 35551662 DOI: 10.1007/978-3-030-96376-7_8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Acute myeloid leukemia (AML) is an aggressive, clonally heterogeneous, myeloid malignancy, with a 5-year overall survival of approximately 27%. It constitutes the most common acute leukemia in adults, with an incidence of 3-5 cases per 100,000 in the United States. Despite great advances in understanding the molecular mechanisms underpinning leukemogenesis, the past several decades had seen little change to the backbone of therapy, comprised of an anthracycline-based induction regimen for those who are fit enough to receive it, followed by risk-stratified post-remission therapy with consolidation cytarabine or allogeneic stem cell transplantation (allo-SCT). Allo-SCT is the most fundamental form of immunotherapy in which donor cytotoxic T and NK cells recognize and eradicate residual AML in the graft-versus-leukemia (GvL) effect. Building on that, several alternative or synergistic approaches to exploit both self and foreign immunity against AML have been developed. Checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors block proteins found on T cells or cancer cells that stop the immune system from attacking the cancer cells. They have been used with limited success in both the AML relapsed/refractory (R/R) and post SCT settings. AML tumor mutational burden is low compared to solid tumors and thus, it is less likely to generate neoantigens and respond to antibody-mediated checkpoint blockade that has shown unprecedented results in solid tumors. Therefore, alternative therapeutic strategies that work independently of the T cell receptor (TCR) specificity have been developed. They include bispecific antibodies, which recruit T cells through CD3 engagement, and in AML have shown an overall response rate ranging between 14 and 30% in early phase trials. Chimeric Antigen Receptor (CAR) T cell therapy is a type of treatment in which T cells are genetically engineered to produce a recombinant receptor that redirects the specificity and function of T lymphocytes. However, lack of cell surface targets exclusively expressed on AML cells including Leukemic Stem Cells (LSCs) combined with clonal heterogeneity represents the biggest challenge in developing CAR therapy for AML. Antibody-Drug Conjugates (ADC) constitute the only FDA-approved immunotherapy to treat AML with Gemtuzumab Ozogamicin, a CD33-specific ADC used in CEBPα-mutated AML. The identification of additional cell surface targets is critical for the development of other ADC's potentially useful in the induction and maintenance regimens, given the ease at which these reagents can be generated and managed. Here, we will review those immune-based therapeutic interventions and highlight active areas of research investigations toward fulfillment of the great promise of immunotherapy to AML.
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Affiliation(s)
- Fabiana Perna
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, USA.
| | - Manuel R Espinoza-Gutarra
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, USA
| | - Giuseppe Bombaci
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, USA
| | - Sherif S Farag
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, USA
| | - Jennifer E Schwartz
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, USA
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5
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Szöőr Á, Szöllősi J, Vereb G. From antibodies to living drugs: Quo vadis cancer immunotherapy? Biol Futur 2021; 72:85-99. [PMID: 34554498 DOI: 10.1007/s42977-021-00072-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/12/2021] [Indexed: 01/16/2023]
Abstract
In the last few decades, monoclonal antibodies targeting various receptors and ligands have shown significant advance in cancer therapy. However, still a great percentage of patients experiences tumor relapse despite persistent antigen expression. Immune cell therapy with adoptively transferred modified T cells that express chimeric antigen receptors (CAR) is an engaging option to improve disease outcome. Designer T cells have been applied with remarkable success in the treatment for acute B cell leukemias, yielding unprecedented antitumor activity and significantly improved overall survival. Relying on the success of CAR T cells in leukemias, solid tumors are now emerging potential targets; however, their complexity represents a significant challenge. In preclinical models, CAR T cells recognized and efficiently killed the wide spectrum of tumor xenografts; however, in human clinical trials, limited antitumor efficacy and serious side effects, including cytokine release syndrome, have emerged as potential limitations. The next decade will be an exciting time to further optimize this novel cellular therapeutics to improve effector functions and, at the same time, keep adverse events in check. Moreover, we need to establish whether gene-modified T cells which are yet exclusively used for cancer patients could also be successful in the treatment for other diseases. Here, we provide a concise overview about the transition from monoclonal antibodies to the generation of chimeric antigen receptor T cells. We summarize lessons learned from preclinical models, including our own HER2-positive tumor models, as well as from clinical trials worldwide. We also discuss the challenges we are facing today and outline future prospects.
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Affiliation(s)
- Árpád Szöőr
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary
| | - János Szöllősi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary
| | - György Vereb
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary.
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary.
- Faculty of Pharmacy, University of Debrecen, Egyetem tér 1., 4032, Debrecen, Hungary.
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6
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Agrawal V, Gbolahan OB, Stahl M, Zeidan AM, Zaid MA, Farag SS, Konig H. Vaccine and Cell-based Therapeutic Approaches in Acute Myeloid Leukemia. Curr Cancer Drug Targets 2021; 20:473-489. [PMID: 32357813 DOI: 10.2174/1568009620666200502011059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 03/05/2020] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Over the past decade, our increased understanding of the interactions between the immune system and cancer cells has led to paradigm shifts in the clinical management of solid and hematologic malignancies. The incorporation of immune-targeted strategies into the treatment landscape of acute myeloid leukemia (AML), however, has been challenging. While this is in part due to the inability of the immune system to mount an effective tumor-specific immunogenic response against the heterogeneous nature of AML, the decreased immunogenicity of AML cells also represents a major obstacle in the effort to design effective immunotherapeutic strategies. In fact, AML cells have been shown to employ sophisticated escape mechanisms to evade elimination, such as direct immunosuppression of natural killer cells and decreased surface receptor expression leading to impaired recognition by the immune system. Yet, cellular and humoral immune reactions against tumor-associated antigens (TAA) of acute leukemia cells have been reported and the success of allogeneic stem cell transplantation and monoclonal antibodies in the treatment of AML clearly provides proof that an immunotherapeutic approach is feasible in the management of this disease. This review discusses the recent progress and persisting challenges in cellular immunotherapy for patients with AML.
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Affiliation(s)
- Vaibhav Agrawal
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Olumide B Gbolahan
- Division of Hematology and Oncology, University of Alabama School of Medicine, Birmingham, AL 35294, United States
| | - Maximilian Stahl
- Department of Medicine, Division of Hematology and Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
| | - Amer M Zeidan
- Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Mohammad Abu Zaid
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Sherif S Farag
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Heiko Konig
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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7
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Chen J, Zhang H, Zhou L, Hu Y, Li M, He Y, Li Y. Enhancing the Efficacy of Tumor Vaccines Based on Immune Evasion Mechanisms. Front Oncol 2021; 10:584367. [PMID: 33614478 PMCID: PMC7886973 DOI: 10.3389/fonc.2020.584367] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor vaccines aim to expand tumor-specific T cells and reactivate existing tumor-specific T cells that are in a dormant or unresponsive state. As such, there is growing interest in improving the durable anti-tumor activity of tumor vaccines. Failure of vaccine-activated T cells to protect against tumors is thought to be the result of the immune escape mechanisms of tumor cells and the intricate immunosuppressive tumor microenvironment. In this review, we discuss how tumor cells and the tumor microenvironment influence the effects of tumor infiltrating lymphocytes and summarize how to improve the efficacy of tumor vaccines by improving the design of current tumor vaccines and combining tumor vaccines with other therapies, such as metabolic therapy, immune checkpoint blockade immunotherapy and epigenetic therapy.
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Affiliation(s)
- Jianyu Chen
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Honghao Zhang
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lijuan Zhou
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuxing Hu
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Meifang Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yanjie He
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
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8
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Shin MH, Kim J, Lim SA, Kim J, Kim SJ, Lee KM. NK Cell-Based Immunotherapies in Cancer. Immune Netw 2020; 20:e14. [PMID: 32395366 PMCID: PMC7192832 DOI: 10.4110/in.2020.20.e14] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 03/01/2020] [Accepted: 03/01/2020] [Indexed: 12/11/2022] Open
Abstract
With the development of technologies that can transform immune cells into therapeutic modalities, immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. NK cells are components of the innate immune system that act as key regulators and exhibit a potent tumor cytolytic function. Unlike T cells, NK cells exhibit tumor cytotoxicity by recognizing non-self, without deliberate immunization or activation. Currently, researchers have developed various approaches to improve the number and anti-tumor function of NK cells. These approaches include the use of cytokines and Abs to stimulate the efficacy of NK cell function, adoptive transfer of autologous or allogeneic ex vivo expanded NK cells, establishment of homogeneous NK cell lines using the NK cells of patients with cancer or healthy donors, derivation of NK cells from induced pluripotent stem cells (iPSCs), and modification of NK cells with cutting-edge genetic engineering technologies to generate chimeric Ag receptor (CAR)-NK cells. Such NK cell-based immunotherapies are currently reported as being promising anti-tumor strategies that have shown enhanced functional specificity in several clinical trials investigating malignant tumors. Here, we summarize the recent advances in NK cell-based cancer immunotherapies that have focused on providing improved function through the use of the latest genetic engineering technologies. We also discuss the different types of NK cells developed for cancer immunotherapy and present the clinical trials being conducted to test their safety and efficacy.
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Affiliation(s)
- Min Hwa Shin
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Junghee Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Siyoung A Lim
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Jungwon Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Seong-Jin Kim
- Precision Medicine Research Center, Advanced Institutes of Convergence Technology, Seoul National University, Suwon 16229, Korea
| | - Kyung-Mi Lee
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
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9
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Onodi F, Maherzi-Mechalikh C, Mougel A, Ben Hamouda N, Taboas C, Gueugnon F, Tran T, Nozach H, Marcon E, Gey A, Terme M, Bouzidi A, Maillere B, Kerzerho J, Tartour E, Tanchot C. High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4 + and CD8 + T-Cell Epitopes. Front Oncol 2018; 8:517. [PMID: 30483475 PMCID: PMC6243131 DOI: 10.3389/fonc.2018.00517] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/22/2018] [Indexed: 12/22/2022] Open
Abstract
The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development.
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Affiliation(s)
- Fanny Onodi
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France
| | - Chahrazed Maherzi-Mechalikh
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Alice Mougel
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Nadine Ben Hamouda
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.,Service d'immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Charlotte Taboas
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France
| | - Fabien Gueugnon
- VAXEAL Research, Evry, France.,CEA-Saclay, Institut des Sciences du Vivant Frederic Joliot, Service d'Ingénierie Moléculaire des Protéines, Gif Sur Yvette, France
| | - Thi Tran
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France
| | - Herve Nozach
- CEA-Saclay, Institut des Sciences du Vivant Frederic Joliot, Service d'Ingénierie Moléculaire des Protéines, Gif Sur Yvette, France
| | - Elodie Marcon
- CEA-Saclay, Institut des Sciences du Vivant Frederic Joliot, Service d'Ingénierie Moléculaire des Protéines, Gif Sur Yvette, France
| | - Alain Gey
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.,Service d'immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Magali Terme
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | | | - Bernard Maillere
- CEA-Saclay, Institut des Sciences du Vivant Frederic Joliot, Service d'Ingénierie Moléculaire des Protéines, Gif Sur Yvette, France
| | | | - Eric Tartour
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Service d'immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Corinne Tanchot
- INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France
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10
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Mirzaei HR, Mirzaei H, Namdar A, Rahmati M, Till BG, Hadjati J. Predictive and therapeutic biomarkers in chimeric antigen receptor T‐cell therapy: A clinical perspective. J Cell Physiol 2018; 234:5827-5841. [DOI: 10.1002/jcp.27519] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 09/10/2018] [Indexed: 12/31/2022]
Affiliation(s)
- Hamid Reza Mirzaei
- Department of Medical Immunology School of Medicine, Tehran University of Medical Sciences Tehran Iran
| | - Hamed Mirzaei
- Department of Medical Biotechnology School of Medicine, Mashhad University of Medical Sciences Mashahd Iran
| | - Afshin Namdar
- Department of Dentistry Faculty of Medicine and Dentistry, University of Alberta Edmonton Canada
| | - Majid Rahmati
- Cancer Prevention Research Center Shahroud University of Medical Sciences Shahroud Iran
| | - Brian G. Till
- Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA United States
| | - Jamshid Hadjati
- Department of Medical Immunology School of Medicine, Tehran University of Medical Sciences Tehran Iran
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11
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Park YJ, Kuen DS, Chung Y. Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance. Exp Mol Med 2018; 50:1-13. [PMID: 30135516 PMCID: PMC6105674 DOI: 10.1038/s12276-018-0130-1] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/30/2018] [Accepted: 05/15/2018] [Indexed: 12/22/2022] Open
Abstract
Recent advances in the understating of tumor immunology suggest that cancer immunotherapy is an effective treatment against various types of cancer. In particular, the remarkable successes of immune checkpoint-blocking antibodies in clinical settings have encouraged researchers to focus on developing other various immunologic strategies to combat cancer. However, such immunotherapies still face difficulties in controlling malignancy in many patients due to the heterogeneity of both tumors and individual patients. Here, we discuss how tumor-intrinsic cues, tumor environmental metabolites, and host-derived immune cells might impact the efficacy and resistance often seen during immune checkpoint blockade treatment. Furthermore, we introduce biomarkers identified from human and mouse models that predict clinical benefits for immune checkpoint blockers in cancer.
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Affiliation(s)
- Young-Jun Park
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- BK21 Plus program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
| | - Da-Sol Kuen
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- BK21 Plus program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
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12
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Abstract
Chimeric antigen receptor (CAR) T-cells are redirected T-cells that can recognize cancer antigens in a major histocompatibility complex (MHC)-independent fashion. A typical CAR is comprised of two main functional domains: an extracellular antigen recognition domain, called a single-chain variable fragment (scFv), and an intracellular signaling domain. Based on the number of intracellular signaling molecules, CARs are categorized into four generations. CAR T-cell therapy has become a promising treatment for hematologic malignancies. However, results of its clinical trials on solid tumors have not been encouraging. Here, we described the structure of CARs and summarized the clinical trials of CD19-targeted CAR T-cells. The side effects, safety management, challenges, and future prospects of CAR T-cells for the treatment of cancer, particularly for solid tumors, were also discussed.
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Affiliation(s)
- Niaz Muhammad
- a Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences , Shaanxi Normal University , Xi'an , P.R. China
| | - Qinwen Mao
- b Department of Pathology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA
| | - Haibin Xia
- a Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences , Shaanxi Normal University , Xi'an , P.R. China
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13
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Perna F, Berman SH, Soni RK, Mansilla-Soto J, Eyquem J, Hamieh M, Hendrickson RC, Brennan CW, Sadelain M. Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML. Cancer Cell 2017; 32:506-519.e5. [PMID: 29017060 PMCID: PMC7025434 DOI: 10.1016/j.ccell.2017.09.004] [Citation(s) in RCA: 252] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 08/02/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38- hematopoietic cells, T cells, or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.
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Affiliation(s)
- Fabiana Perna
- Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Samuel H Berman
- Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rajesh K Soni
- Microchemistry and Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Jorge Mansilla-Soto
- Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Justin Eyquem
- Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mohamad Hamieh
- Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ronald C Hendrickson
- Microchemistry and Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Cameron W Brennan
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michel Sadelain
- Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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14
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Abstract
INTRODUCTION Recent breakthrough advances in Multiple Myeloma (MM) immunotherapy have been achieved with the approval of the first two monoclonal antibodies, elotuzumab and daratumumab. Adoptive cell therapy (ACT) represents yet another, maybe the most powerful modality of immunotherapy, in which allogeneic or autologous effector cells are expanded and activated ex vivo followed by their re-infusion back into patients. Infused effector cells belong to two categories: naturally occurring, non-engineered cells (donor lymphocyte infusion, myeloma infiltrating lymphocytes, deltagamma T cells) or genetically- engineered antigen-specific cells (chimeric antigen receptor T or NK cells, TCR-engineered cells). Areas covered: This review article summarizes our up-to-date knowledge on ACT in MM, its promises, and upcoming strategies to both overcome its toxicity and to integrate it into future treatment paradigms. Expert opinion: Early results of clinical studies using CAR T cells or TCR- engineered T cells in relapsed and refractory MM are particularly exciting, indicating the potential of long-term disease control or even cure. Despite several caveats including toxicity, costs and restricted availability in particular, these forms of immunotherapy are likely to once more revolutionize MM therapy.
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Affiliation(s)
- Sonia Vallet
- a Department of Internal Medicine , Karl Landsteiner University of Health Sciences, University Hospital , Krems an der Donau , Austria
| | - Martin Pecherstorfer
- a Department of Internal Medicine , Karl Landsteiner University of Health Sciences, University Hospital , Krems an der Donau , Austria
| | - Klaus Podar
- a Department of Internal Medicine , Karl Landsteiner University of Health Sciences, University Hospital , Krems an der Donau , Austria
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15
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[Immunotherapy: Activation of a system not a pathway]. Bull Cancer 2017; 104:462-475. [PMID: 28477871 DOI: 10.1016/j.bulcan.2017.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 03/02/2017] [Accepted: 03/04/2017] [Indexed: 11/22/2022]
Abstract
Immunotherapy is on the roll. After revolutionary effects in melanoma, immunotherapy is invading other locations. If current treatments, chemotherapies or targeted therapies block one pathway, immunotherapy should be understood as the activation of a whole system. Indeed, oncogenesis process is defined as an escape of the immune system and the stimulation of this system can block the carcinogenic process. The aim of the present review is to describe the place of immunotherapy in the treatment of solid cancers.
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16
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Perna F, Sadelain M. Myeloid leukemia switch as immune escape from CD19 chimeric antigen receptor (CAR) therapy. Transl Cancer Res 2016; 5:S221-S225. [PMID: 28824851 DOI: 10.21037/tcr.2016.08.15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Fabiana Perna
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michel Sadelain
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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17
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Domschke C, Schneeweiss A, Stefanovic S, Wallwiener M, Heil J, Rom J, Sohn C, Beckhove P, Schuetz F. Cellular Immune Responses and Immune Escape Mechanisms in Breast Cancer: Determinants of Immunotherapy. Breast Care (Basel) 2016; 11:102-7. [PMID: 27239171 DOI: 10.1159/000446061] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
More recently, immunotherapy has emerged as a novel potentially effective therapeutic option also for solid malignancies such as breast cancer (BC). Relevant approaches, however, are determined by the 2 main elements of cancer immunoediting - the elimination of nascent transformed cells by immunosurveillance on the one hand and tumor immune escape on the other hand. Correspondingly, we here review the role of the various cellular immune players within the host-protective system and dissect the mechanisms of immune evasion leading to tumor progression. If the immune balance of disseminated BC cell dormancy (equilibrium phase) is lost, distant metastatic relapse may occur. The relevant cellular antitumor responses and translational immunotherapeutic options will also be discussed in terms of clinical benefit and future directions in BC management.
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Affiliation(s)
- Christoph Domschke
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Andreas Schneeweiss
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Stefan Stefanovic
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Markus Wallwiener
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Joerg Heil
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Joachim Rom
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Christof Sohn
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Philipp Beckhove
- Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, Regensburg, Germany
| | - Florian Schuetz
- Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany
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18
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Dai H, Wang Y, Lu X, Han W. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy. J Natl Cancer Inst 2016; 108:djv439. [PMID: 26819347 PMCID: PMC4948566 DOI: 10.1093/jnci/djv439] [Citation(s) in RCA: 201] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy.
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Affiliation(s)
- Hanren Dai
- Affiliations of authors: Department of Immunology (HD, YW, WH) and Department of Molecular Biology (WH), Institute of Basic Medicine, School of Life Sciences, Department of Bio-therapeutic (HD, YW, WH), and Department of Hematology (XL), Chinese PLA General Hospital, Beijing, China
| | - Yao Wang
- Affiliations of authors: Department of Immunology (HD, YW, WH) and Department of Molecular Biology (WH), Institute of Basic Medicine, School of Life Sciences, Department of Bio-therapeutic (HD, YW, WH), and Department of Hematology (XL), Chinese PLA General Hospital, Beijing, China
| | - Xuechun Lu
- Affiliations of authors: Department of Immunology (HD, YW, WH) and Department of Molecular Biology (WH), Institute of Basic Medicine, School of Life Sciences, Department of Bio-therapeutic (HD, YW, WH), and Department of Hematology (XL), Chinese PLA General Hospital, Beijing, China
| | - Weidong Han
- Affiliations of authors: Department of Immunology (HD, YW, WH) and Department of Molecular Biology (WH), Institute of Basic Medicine, School of Life Sciences, Department of Bio-therapeutic (HD, YW, WH), and Department of Hematology (XL), Chinese PLA General Hospital, Beijing, China.
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19
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Abstract
Twenty-five years after its inception, the genetic engineering of T cells is now a therapeutic modality pursued at an increasing number of medical centers. This immunotherapeutic strategy is predicated on gene transfer technology to instruct T lymphocytes to recognize and reject tumor cells. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and - in the case of second-generation CARs - costimulation to augment T cell functionality and persistence. We demonstrated over a decade ago that human T cells engineered with a CD19-specific CAR eradicated B cell malignancies in mice. Several phase I clinical trials eventually yielded dramatic results in patients with leukemia or lymphoma, especially acute lymphoblastic leukemia (ALL). This review recounts the milestones of CD19 CAR therapy and summarizes lessons learned from the CD19 paradigm.
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20
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Heiblig M, Elhamri M, Michallet M, Thomas X. Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors. World J Stem Cells 2015; 7:1022-1038. [PMID: 26328018 PMCID: PMC4550626 DOI: 10.4252/wjsc.v7.i7.1022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 12/28/2014] [Accepted: 06/19/2015] [Indexed: 02/06/2023] Open
Abstract
Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90’s, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding “living drug” specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.
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21
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Linch SN, McNamara MJ, Redmond WL. OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal. Front Oncol 2015; 5:34. [PMID: 25763356 PMCID: PMC4329814 DOI: 10.3389/fonc.2015.00034] [Citation(s) in RCA: 183] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 01/30/2015] [Indexed: 12/24/2022] Open
Abstract
Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as “checkpoint inhibitors,” can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the “brakes” on T cells to boost anti-tumor immunity. Generating optimal “killer” CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.
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Affiliation(s)
- Stefanie N Linch
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center , Portland, OR , USA
| | - Michael J McNamara
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center , Portland, OR , USA
| | - William L Redmond
- Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center , Portland, OR , USA
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22
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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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23
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Budhu S, Wolchok J, Merghoub T. The importance of animal models in tumor immunity and immunotherapy. Curr Opin Genet Dev 2013; 24:46-51. [PMID: 24657536 DOI: 10.1016/j.gde.2013.11.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Revised: 11/06/2013] [Accepted: 11/13/2013] [Indexed: 01/16/2023]
Abstract
The clinical success and US FDA approval of two immunotherapies (sipuleucel-T and ipilimumab) have brought tumor immunology to the forefront of cancer research. It has been long recognized that the immune system can infiltrate and survey the tumor microenvironment. The field of tumor immunology has been actively examining this phenomenon since the 1890s when William Coley first treated patients with live pathogenic bacteria and observed occasional regressions leading to long term survival. Recent progress in understanding mechanisms of immune activation and tolerance has led to the development of novel therapies that aim to either overcome inhibitory pathways (i.e. checkpoint blockade such as anti-CTLA-4 and anti-PD-1) or stimulate immune cell activation (i.e. co-stimulation such as anti-GITR and anti-OX40). A major part of the success of immunotherapy has been the development of appropriate mouse models. This review will outline the history and the major findings leading to the accomplishments of modern day immunology with specific attention to the usefulness of animal models.
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Affiliation(s)
- Sadna Budhu
- Ludwig Collaborative Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States
| | - Jedd Wolchok
- Ludwig Collaborative Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States; Weill Cornell Medical College, New York, NY 10065, United States
| | - Taha Merghoub
- Ludwig Collaborative Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States.
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24
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Schad F, Atxner J, Buchwald D, Happe A, Popp S, Kröz M, Matthes H. Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma: A Retrospective Analysis. Integr Cancer Ther 2013; 13:332-40. [PMID: 24363283 DOI: 10.1177/1534735413513637] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pancreatic carcinoma remains one of the main causes for cancer-related death. Intratumoral application of anticancer agents is discussed as a promising method for solid tumors such as pancreatic cancer. Endoscopic ultrasound provides a good tool to examine and treat the pancreas. European mistletoe (Viscum album L) is a phytotherapeutic commonly used in integrative oncology in Central Europe. Its complementary use seeks to induce immunostimulation and antitumoral effects as well as alleviate chemotherapeutic side effects. Intratumoral mistletoe application has induced local tumor response in various cancer entities. This off-label use needs to be validated carefully in terms of safety and benefits. Here we report on 39 patients with advanced, inoperable pancreatic cancer, who received in total 223 intratumoral applications of mistletoe, endoscopic ultrasound guided or under transabdominal ultrasound control. No severe procedure-related events were reported. Adverse drug reactions were mainly increased body temperature or fever in 14% and 11% of the applications, respectively. Other adverse drug reactions, such as pain or nausea, occurred in less than 7% of the procedures. No severe adverse drug reaction was recorded. Patients received standard first- and second-line chemotherapy and underwent adequate palliative surgical interventions as well as additive subcutaneous and partly intravenous mistletoe application. A median survival of 11 months was observed for all patients, or 11.8 and 8.3 months for stages III and IV, respectively. Due to the multimodal therapeutic setting and the lack of a control group, the effect of intratumoral mistletoe administration alone remains unclear. This retrospective analysis suggests that intratumoral-applicated mistletoe might contribute to improve survival of patients with pancreatic cancer. In conclusion, the application is feasible and safe, and its efficacy should be evaluated in a randomized controlled trial.
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Affiliation(s)
- Friedemann Schad
- Hospital Havelhoehe, Berlin, Germany Research Institute Havelhoehe, Berlin, Germany
| | - Jan Atxner
- Research Institute Havelhoehe, Berlin, Germany
| | | | - Antje Happe
- Research Institute Havelhoehe, Berlin, Germany
| | | | - Matthias Kröz
- Hospital Havelhoehe, Berlin, Germany Research Institute Havelhoehe, Berlin, Germany
| | - Harald Matthes
- Hospital Havelhoehe, Berlin, Germany Research Institute Havelhoehe, Berlin, Germany
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25
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26
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Geng R, Song F, Yang X, Sun P, Hu J, Zhu C, Zhu B, Fan W. Association between cytotoxic T lymphocyte antigen-4 +49A/G, -1722T/C, and -1661A/G polymorphisms and cancer risk: a meta-analysis. Tumour Biol 2013; 35:3627-39. [PMID: 24307627 DOI: 10.1007/s13277-013-1480-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 11/26/2013] [Indexed: 01/08/2023] Open
Abstract
Cytotoxic T lymphocyte antigen-4 (CTLA-4), a key gene that contributes to the susceptibility and clinical course of cancer, is an important down-regulator of T cell activation and proliferation. The +49A/G polymorphism is commonly studied because of its association with cancer risks. However, other polymorphisms, such as -1722T/C and -1661A/G, have not been studied in detail. We performed a meta-analysis using 43 eligible case-control studies with a total of 19,089 patients and 21,388 controls to examine the association between CTLA-4 +49A/G, -1722T/C, and -1661A/G polymorphisms and cancer risk. We searched the PubMed and EMBASE databases for all articles published up to July 17, 2013. Individuals with the +49 A allele (AA/AG vs. GG, odds ratio (OR) = 1.21, 95% confidence interval (95% CI) = 1.16-1.27) and -1661 G allele (AG/GG vs. AA, OR = 1.52, 95% CI = 1.34-1.73) had increased cancer risk. However, no significant association between cancer risk and the -1722T/C polymorphism was found (CC/CT vs. TT, OR = 1.04, 95% CI = 0.92-1.16). In subgroup analysis for the +49A/G polymorphism, increased cancer risk remained in the subgroups of Asians (OR = 1.25, 95 % CI = 1.18-1.31), patients with breast cancer (OR = 1.28, 95% CI = 1.15-1.42), and patients with lung cancer (OR = 1.20, 95 % CI = 1.07-1.35). For the -1661A/G polymorphism, increased cancer risk remained in the subgroups of Asians (OR = 1.52, 95% CI = 1.34-1.73), patients with breast cancer (OR = 1.48, 95% CI = 1.07-2.03), and patients with oral cancer (OR = 3.16, 95% CI = 1.84-5.45). However, no significant increase in cancer risk was found in the subgroups for the -1722T/C polymorphism. In conclusion, the results suggest that +49A/G and -1661A/G polymorphisms in CTLA-4 are risk factors for cancers, whereas the -1722T/C polymorphism is not associated with an increased risk of cancer.
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Affiliation(s)
- Rui Geng
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China,
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27
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Heidegger I, Massoner P, Eder IE, Pircher A, Pichler R, Aigner F, Bektic J, Horninger W, Klocker H. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer. J Steroid Biochem Mol Biol 2013; 138:248-56. [PMID: 23792785 PMCID: PMC3834152 DOI: 10.1016/j.jsbmb.2013.06.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 05/28/2013] [Accepted: 06/04/2013] [Indexed: 11/10/2022]
Abstract
Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.
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Affiliation(s)
- Isabel Heidegger
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Petra Massoner
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Iris E. Eder
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Andreas Pircher
- Department of Hematology and Oncology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Renate Pichler
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Friedrich Aigner
- Department of Radiology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Jasmin Bektic
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Wolfgang Horninger
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Helmut Klocker
- Department of Urology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
- Corresponding author at: Department of Urology, Division of Experimental Urology, Anichstrasse 35, 6020 Innsbruck, Austria. Tel.: +43 512 504 24818; fax: +43 512 504 24817.
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Mohsenzadegan M, Madjd Z, Asgari M, Abolhasani M, Shekarabi M, Taeb J, Shariftabrizi A. Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis. Cancer Immunol Immunother 2013; 62:1609-18. [PMID: 23955683 PMCID: PMC11029587 DOI: 10.1007/s00262-013-1463-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 08/03/2013] [Indexed: 10/26/2022]
Abstract
New gene expressed in prostate (NGEP) is a newly diagnosed prostate-specific gene that is expressed only in normal prostate and prostate cancer cells. Discovery of tissue-specific markers may promote the development of novel targets for immunotherapy of prostate cancer. In the present study, the staining pattern and clinical significance of NGEP were evaluated in a series of prostate tissues composed of 123 prostate cancer, 19 high-grade prostatic intraepithelial neoplasia and 44 samples of benign prostate tissue included in tissue microarrays using immunohistochemistry. Our study demonstrated that NGEP localized mainly in the apical and lateral membranes and was also partially distributed in the cytoplasm of epithelial cells of normal prostate tissue. All of the examined prostate tissues expressed NGEP with a variety of intensities; the level of expression was significantly more in the benign prostate tissues compared to malignant prostate samples (P value <0.001). Among prostate adenocarcinoma samples, a significant and inverse correlation was observed between the intensity of NGEP expression and increased Gleason score (P = 0.007). Taken together, we found that NGEP protein is widely expressed in low-grade to high-grade prostate adenocarcinomas as well as benign prostate tissues, and the intensity of expression is inversely proportional to the level of malignancy. NGEP could be an attractive target for immune-based therapy of prostate cancer patients as an alternative to the conventional therapies particularly in indolent patients.
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Affiliation(s)
- Monireh Mohsenzadegan
- Immunology Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Department of Pathology, Oncopathology Research Centre, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, 14496-14530 Tehran, Iran
- Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojgan Asgari
- Department of Pathology, Oncopathology Research Centre, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, 14496-14530 Tehran, Iran
- Department of Pathology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Abolhasani
- Department of Pathology, Oncopathology Research Centre, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, 14496-14530 Tehran, Iran
- Department of Pathology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Shekarabi
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Jaleh Taeb
- Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ahmad Shariftabrizi
- Department of Pathology, Oncopathology Research Centre, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, 14496-14530 Tehran, Iran
- Department of Pathology, Danbury Hospital, Yale University, Danbury, CT 06810 USA
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Taraban VY, Rowley TF, Kerr JP, Willoughby JE, Johnson PMW, Al-Shamkhani A, Buchan SL. CD27 costimulation contributes substantially to the expansion of functional memory CD8(+) T cells after peptide immunization. Eur J Immunol 2013; 43:3314-23. [PMID: 24002868 DOI: 10.1002/eji.201343579] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 07/19/2013] [Accepted: 08/29/2013] [Indexed: 12/22/2022]
Abstract
Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8(+) T-cell reactivation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8(+) T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C, or LPS, requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (soluble recombinant CD70 (sCD70)), is sufficient for secondary memory CD8(+) T-cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector- and central-memory CD8(+) T cells both expressed CD27 with greater expression on central memory cells. Nonetheless, both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with Ag and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8(+) T-cell activation to a peptide Ag, and identify sCD70 as an immunotherapeutic adjuvant for antitumor immunity.
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Affiliation(s)
- Vadim Y Taraban
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
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Zigler M, Shir A, Levitzki A. Targeted cancer immunotherapy. Curr Opin Pharmacol 2013; 13:504-10. [DOI: 10.1016/j.coph.2013.04.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 04/03/2013] [Accepted: 04/04/2013] [Indexed: 12/30/2022]
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Stead RE, Fox MA, Staples E, Lim CS. Delayed presentation of melanoma-associated retinopathy and subsequent resolution with cytoreduction surgery. Doc Ophthalmol 2013; 127:165-71. [PMID: 23794161 DOI: 10.1007/s10633-013-9398-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 06/10/2013] [Indexed: 11/27/2022]
Abstract
BACKGROUND To present a case of melanoma-associated retinopathy (MAR) which manifested 26 months prior to a formal diagnosis of melanoma. METHODS Case report. RESULTS A 72-year-old female presented with bilateral continuous photopsia consistent with MAR of 7-months duration. At this point, visual function appeared normal with the exception of mildly impaired colour vision (10/17 Ishihara plates). The flash electroretinographic (ERG) revealed extinguished rod responses, a normal a-wave and reduced b-wave (electronegative ERG) on the maximal combined response, absent oscillatory potentials and broadened a-wave trough on the cone response. Multifocal ERG (mfERG) responses were delayed and demonstrated atypical morphology. Nineteen months after the initial presentation, her visual symptoms had progressed significantly with constant debilitating photopsia in combination with 13 kg weight loss. Biopsy of a now evident left axillary mass demonstrated a metastatic high-grade malignant melanoma. No primary was detected, and an axillary lymph node clearance was undertaken. Subsequently, visual symptoms resolved with corresponding improvement in the ERG over the next 18 months. Rod responses recovered such that the amplitude was at the lower limit of normal and the mfERG response delay lessened. Unfortunately, the melanoma recurred and the patient passed away 6 months later. Visual symptoms did not recur. CONCLUSION We present a case which demonstrates MAR may precede the formal diagnosis of melanoma by up to 26 months. The potential for improvement in the rod visual function persists over a period of years with normalisation of an electronegative waveform. In this case, cytoreductive surgery resulted in complete resolution of the MAR, which did not return even with a recurrence of the tumour.
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Affiliation(s)
- Richard E Stead
- Department of Ophthalmology, Queens Medical Centre, Nottingham University NHS Trust, Nottingham, NG7 2UH, UK,
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Abstract
UNLABELLED Chimeric antigen receptors (CAR) are recombinant receptors that provide both antigen-binding and T-cell-activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biologic functions have dramatically changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. These have recently shown clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors, or cytokines to further enhance T-cell potency, specificity, and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy. SIGNIFICANCE CARs are a new class of drugs with great potential for cancer immunotherapy. Upon their expression in T lymphocytes, CARs direct potent, targeted immune responses that have recently shown encouraging clinical outcomes in a subset of patients with B-cell malignancies. This review focuses on the design of CARs, including the requirements for optimal antigen recognition and different modalities to provide costimulatory support to targeted T cells, which include the use of second- and third generation CARs, costimulatory ligands, chimeric costimulatory receptors, and cytokines.
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Affiliation(s)
- Michel Sadelain
- Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
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Chimal-Ramírez GK, Espinoza-Sánchez NA, Fuentes-Pananá EM. Protumor activities of the immune response: insights in the mechanisms of immunological shift, oncotraining, and oncopromotion. JOURNAL OF ONCOLOGY 2013; 2013:835956. [PMID: 23577028 PMCID: PMC3612474 DOI: 10.1155/2013/835956] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 01/25/2013] [Indexed: 12/15/2022]
Abstract
Experimental and clinical studies indicate that cells of the innate and adaptive immune system have both anti- and pro-tumor activities. This dual role of the immune system has led to a conceptual shift in the role of the immune system's regulation of cancer, in which immune-tumor cell interactions are understood as a dynamic process that comprises at least five phases: immunosurveillance, immunoselection, immunoescape, oncotraining, and oncopromotion. The tumor microenvironment shifts immune cells to perform functions more in tune with the tumor needs (oncotraining); these functions are related to chronic inflammation and tissue remodeling activities. Among them are increased proliferation and survival, increased angiogenesis and vessel permeability, protease secretion, acquisition of migratory mesenchymal characteristics, and self-renewal properties that altogether promote tumor growth and metastasis (oncopromotion). Important populations in all these pro-tumor processes are M2 macrophages, N2 neutrophils, regulatory T cells, and myeloid derived suppressor cells; the main effectors molecules are CSF-1, IL-6, metalloproteases, VEGF, PGE-2, TGF- β , and IL-10. Cancer prognosis correlates with densities and concentrations of protumoral populations and molecules, providing ideal targets for the intelligent design of directed preventive or anticancer therapies.
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Affiliation(s)
- G. K. Chimal-Ramírez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Colonia Doctores, 06725 Delegación Cuauhtémoc, DF, Mexico
- Programa de Doctorado en Ciencias Quimicobiológicas del Instituto Politécnico Nacional (IPN), Mexico
| | - N. A. Espinoza-Sánchez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Colonia Doctores, 06725 Delegación Cuauhtémoc, DF, Mexico
- Programa de Doctorado en Ciencias Biomédicas de la Universidad Autónoma de México (UNAM), Mexico
| | - E. M. Fuentes-Pananá
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Colonia Doctores, 06725 Delegación Cuauhtémoc, DF, Mexico
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Chitin, chitosan, and glycated chitosan regulate immune responses: the novel adjuvants for cancer vaccine. Clin Dev Immunol 2013; 2013:387023. [PMID: 23533454 PMCID: PMC3603646 DOI: 10.1155/2013/387023] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 12/22/2012] [Accepted: 12/26/2012] [Indexed: 01/17/2023]
Abstract
With the development of cancer immunotherapy, cancer vaccine has become a novel modality for cancer treatment, and the important role of adjuvant has been realized recently. Chitin, chitosan, and their derivatives have shown their advantages as adjuvants for cancer vaccine. In this paper, the adjuvant properties of chitin and chitosan were discussed, and some detailed information about glycated chitosan and chitosan nanoparticles was also presented to illustrate the trend for future development.
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Mullins CS, Walter A, Schmitt M, Classen CF, Linnebacher M. Tumor antigen and MHC expression in glioma cells for immunotherapeutic interventions. World J Immunol 2013; 3:62. [DOI: 10.5411/wji.v3.i3.62] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 09/15/2013] [Accepted: 11/03/2013] [Indexed: 02/05/2023] Open
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