-
Cancer Cell Oct 2020T cells engineered to express chimeric antigen receptors (CARs) with tumor specificity have shown remarkable success in treating patients with hematologic malignancies... (Review)
Review
T cells engineered to express chimeric antigen receptors (CARs) with tumor specificity have shown remarkable success in treating patients with hematologic malignancies and revitalized the field of adoptive cell therapy. However, realizing broader therapeutic applications of CAR-T cells necessitates engineering approaches on multiple levels to enhance efficacy and safety. Particularly, solid tumors present unique challenges due to the biological complexity of the solid-tumor microenvironment (TME). In this review, we highlight recent strategies to improve CAR-T cell therapy by engineering (1) the CAR protein, (2) T cells, and (3) the interaction between T cells and other components in the TME.
Topics: Animals; Antigens, Neoplasm; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment
PubMed: 32735779
DOI: 10.1016/j.ccell.2020.07.005 -
Clinical and Experimental Immunology May 2020T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging... (Review)
Review
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.
Topics: Antineoplastic Agents, Immunological; Humans; Killer Cells, Natural; Neoplasm Proteins; Neoplasms; Receptors, Immunologic; Receptors, Virus; T-Lymphocytes
PubMed: 31828774
DOI: 10.1111/cei.13407 -
Signal Transduction and Targeted Therapy Jan 2023Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell... (Review)
Review
Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.
Topics: Humans; Neoplasms; Antigens, Neoplasm; Immunotherapy; Cancer Vaccines
PubMed: 36604431
DOI: 10.1038/s41392-022-01270-x -
Frontiers in Immunology 2020The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer... (Review)
Review
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.
Topics: Animals; Biomarkers; Biomarkers, Tumor; Cellular Senescence; Combined Modality Therapy; Disease Management; Disease Progression; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Organ Specificity; Precision Medicine; Prognosis
PubMed: 32849491
DOI: 10.3389/fimmu.2020.01280 -
Cell Aug 2023The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide...
The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.
Topics: Antigens, Neoplasm; Epitopes; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Neoplasms; Proteomics; Receptors, Antigen, T-Cell
PubMed: 37490916
DOI: 10.1016/j.cell.2023.06.020 -
Journal of Hematology & Oncology Mar 2022Research on tumor immunotherapy has made tremendous progress in the past decades, with numerous studies entering the clinical evaluation. The cancer vaccine is... (Review)
Review
Research on tumor immunotherapy has made tremendous progress in the past decades, with numerous studies entering the clinical evaluation. The cancer vaccine is considered a promising therapeutic strategy in the immunotherapy of solid tumors. Cancer vaccine stimulates anti-tumor immunity with tumor antigens, which could be delivered in the form of whole cells, peptides, nucleic acids, etc. Ideal cancer vaccines could overcome the immune suppression in tumors and induce both humoral immunity and cellular immunity. In this review, we introduced the working mechanism of cancer vaccines and summarized four platforms for cancer vaccine development. We also highlighted the clinical research progress of the cancer vaccines, especially focusing on their clinical application and therapeutic efficacy, which might hopefully facilitate the future design of the cancer vaccine.
Topics: Antigens, Neoplasm; Cancer Vaccines; Humans; Immunity, Cellular; Immunotherapy; Neoplasms
PubMed: 35303904
DOI: 10.1186/s13045-022-01247-x -
World Journal of Gastroenterology Sep 2021Incidental pancreatic cysts are commonly encountered with some cysts having malignant potential. The most common pancreatic cystic neoplasms include serous cystadenoma,... (Review)
Review
Incidental pancreatic cysts are commonly encountered with some cysts having malignant potential. The most common pancreatic cystic neoplasms include serous cystadenoma, mucinous cystic neoplasm and intraductal papillary mucinous neoplasm. Risk stratifying pancreatic cysts is important in deciding whether patients may benefit from endoscopic ultrasound (EUS) or surgical resection. Surgery should be reserved for patients with malignant cysts or cysts at high risk for developing malignancy as suggested by various risk features including solid mass, nodule and dilated main pancreatic duct. EUS may supplement magnetic resonance imaging findings for cysts that remain indeterminate or have concerning features on imaging. Various cyst fluid markers including carcinoembryonic antigen, glucose, amylase, cytology, and DNA markers help distinguish mucinous from nonmucinous cysts. This review will guide the practicing gastroenterologist in how to evaluate incidental pancreatic cysts and when to consider referral for EUS or surgery. For presumed low risk cysts, surveillance strategies will be discussed. Managing pancreatic cysts requires an individualized approach that is directed by the various guidelines.
Topics: Cyst Fluid; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Endosonography; Humans; Pancreatic Cyst; Pancreatic Neoplasms
PubMed: 34629795
DOI: 10.3748/wjg.v27.i34.5700 -
Cancer Cell Apr 2020Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the... (Review)
Review
Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.
Topics: Antineoplastic Agents, Immunological; Disease Management; Drug Resistance, Neoplasm; Humans; Immunologic Factors; Immunotherapy; Neoplasms
PubMed: 32289269
DOI: 10.1016/j.ccell.2020.03.017 -
Science Advances Feb 2023T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B... (Review)
Review
T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Antigens, Neoplasm; Cell- and Tissue-Based Therapy
PubMed: 36791198
DOI: 10.1126/sciadv.adf3700 -
Molecular Therapy : the Journal of the... Nov 2020Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading to the... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading to the US Food and Drug Administration (FDA) approval of three CD19-targeted CAR T cell products. In contrast, the clinical experience with CAR T cell therapy for solid tumors and brain tumors has been less encouraging, with only a few patients achieving complete responses. Clinical and preclinical studies have identified multiple "roadblocks," including (1) a limited array of targetable antigens and heterogeneous antigen expression, (2) limited T cell fitness and survival before reaching tumor sites, (3) an inability of T cells to efficiently traffic to tumor sites and penetrate physical barriers, and (4) an immunosuppressive tumor microenvironment. Herein, we review these challenges and discuss strategies that investigators have taken to improve the effector function of CAR T cells for the adoptive immunotherapy of solid tumors.
Topics: Antigens, Neoplasm; Humans; Immunotherapy, Adoptive; Neoplasms; Prognosis; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment
PubMed: 32979309
DOI: 10.1016/j.ymthe.2020.09.015