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Current Opinion in Immunology Dec 2019Immunotherapy of cancer with blockade of inhibitory immune checkpoints and adoptive cell therapies have led to impressive clinical responses in several cancers. However,... (Review)
Review
Immunotherapy of cancer with blockade of inhibitory immune checkpoints and adoptive cell therapies have led to impressive clinical responses in several cancers. However, with increasing utilization of these therapies, immune-related adverse events have emerged as a major obstacle. Herein I discuss recent insights into the immunobiology of these toxicities. Deeper understanding of the underlying pathogenic mechanisms, cellular and molecular pathways involved, similarities and differences with spontaneous autoimmunity, and identification of clinically relevant predictive biomarkers is needed to develop optimal approaches to prevent and treat these toxicities, without compromising the therapeutic benefit from these immune therapies. These events may also provide a unique window into mechanisms underlying spontaneous autoimmunity.
Topics: Animals; Antineoplastic Agents, Immunological; Autoimmune Diseases; Autoimmunity; Biomarkers, Tumor; Disease Models, Animal; Disease Susceptibility; Humans; Immunotherapy, Adoptive; Molecular Targeted Therapy; Neoplasms; Risk Factors
PubMed: 31557690
DOI: 10.1016/j.coi.2019.08.004 -
Cancer Journal (Sudbury, Mass.) 2019Adoptive immunotherapy with engineered T cells is at the forefront of cancer treatment. T cells can be engineered to express T-cell receptors (TCRs) specific for... (Review)
Review
Adoptive immunotherapy with engineered T cells is at the forefront of cancer treatment. T cells can be engineered to express T-cell receptors (TCRs) specific for tumor-associated antigens (TAAs) derived from intracellular or cell surface proteins. T cells engineered with TCRs (TCR-T) allow for targeting diverse types of TAAs, including proteins overexpressed in malignant cells, those with lineage-restricted expression, cancer-testis antigens, and neoantigens created from abnormal, malignancy-restricted proteins. Minor histocompatibility antigens can also serve as TAAs for TCR-T to treat relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Moreover, TCR constructs can be modified to improve safety and enhance function and persistence of TCR-T. Transgenic T-cell receptor therapies targeting 3 different TAAs are in early-phase clinical trials for treatment of hematologic malignancies. Preclinical studies of TCR-T specific for many other TAAs are underway and offer great promise as safe and effective therapies for a wide range of cancers.
Topics: Animals; Antigen Presentation; Antigens, Neoplasm; Disease Susceptibility; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome
PubMed: 31135525
DOI: 10.1097/PPO.0000000000000378 -
Irish Journal of Medical Science Feb 2021Cancer is a major burden on the healthcare system, and new therapies are needed. Recently, the development of immunotherapies, which aim to boost or use the immune... (Review)
Review
Cancer is a major burden on the healthcare system, and new therapies are needed. Recently, the development of immunotherapies, which aim to boost or use the immune system, or its constituents, as a tool to fight malignant cells, has provided a major new tool in the arsenal of clinicians and has revolutionized the treatment of many cancers.Cellular immunotherapies are based on the administration of living cells to patients and have developed hugely, especially since 2010 when Sipuleucel-T (Provenge), a DC vaccine, was the first cellular immunotherapy to be approved by the FDA. The ensuing years have seen two further cellular immunotherapies gain FDA approval: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta).This review will give an overview of the principles of immunotherapies before focusing on the major forms of cellular immunotherapies individually, T cell-based, natural killer (NK) cell-based and dendritic cell (DC)-based, as well as detailing some of the clinical trials relevant to each therapy.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Neoplasms
PubMed: 32607912
DOI: 10.1007/s11845-020-02264-w -
Journal of Hematology & Oncology Jun 2019Chimeric antigen receptor-modified T (CAR-T) cells have achieved significant success in the treatment of several hematological malignancies. However, the translation of... (Review)
Review
Chimeric antigen receptor-modified T (CAR-T) cells have achieved significant success in the treatment of several hematological malignancies. However, the translation of the existing achievements into the treatment of other tumors, especially solid tumors, is not smooth. In addition to the optimization of CAR structures, preparation, and clinical protocols, rational selecting and utilizing the targets was more pivotal. In this review, the criteria for target selection and some new strategies for targets utilization were summarized and discussed. This systematic review will help researchers better understand how the efficacy and safety of CAR-T treatment would be affected by targets and thus more rationally select targets and conduct clinical trials.
Topics: Animals; Humans; Immunity; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 31221182
DOI: 10.1186/s13045-019-0758-x -
Molecular Therapy : the Journal of the... Apr 2019Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected... (Review)
Review
Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected targets present on tumor or infected cells. T cell-based immunotherapy has been progressing over the past several decades, and reached a milestone with the recent US Food and Drug Administration (FDA) approval of chimeric antigen receptor T cell therapy for relapsed and refractory leukemia and lymphoma. Although most studies have used viral vectors, a growing number of researchers have come to appreciate in vitro-transcribed (IVT) mRNA for the development, testing, and application of T cell-based immunotherapeutics. IVT mRNA offers inherent safety features, highly efficient recombinant protein translation, and the ability to control pharmacokinetic properties of the therapy. In this review, we discuss the history of IVT mRNA in adoptive T cell therapy, from tumor-infiltrating lymphocytes and T cell receptor-based therapies to chimeric antigen receptor therapy and gene-editing techniques, as well as prior and ongoing clinical trials.
Topics: Animals; Cell- and Tissue-Based Therapy; Gene Editing; Genetic Vectors; Humans; Immunotherapy, Adoptive; In Vitro Techniques; Lymphocytes, Tumor-Infiltrating; Mice; Neoplasms; RNA, Messenger; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Transcription, Genetic
PubMed: 30819612
DOI: 10.1016/j.ymthe.2019.01.018 -
Cells, Tissues, Organs 2023The past decade has witnessed significant advances in cancer immunotherapy, particularly through the adoptive transfer of engineered T cells in treating advanced... (Review)
Review
The past decade has witnessed significant advances in cancer immunotherapy, particularly through the adoptive transfer of engineered T cells in treating advanced leukemias and lymphomas. Despite these excitements, challenges remain with scale, cost, and ensuring quality control of engineered immune cells, including chimeric antigen receptor T, natural killer cells, and macrophages. The advent of human pluripotent stem cells (hPSCs), including human embryonic stem cells and induced pluripotent stem cells, has transformed immunotherapy by providing a scalable, off-the-shelf source of any desired immune cells for basic research, translational studies, and clinical interventions. The tractability of hPSCs for gene editing could also generate homogenous, universal cellular products with custom functionality for individual or combinatory therapeutic applications. This review will explore various immune cell types whose directed differentiation from hPSCs has been achieved and recently adapted for translational immunotherapy and feature forward-looking bioengineering techniques shaping the future of the stem cell field.
Topics: Humans; Immunotherapy, Adoptive; Pluripotent Stem Cells; Killer Cells, Natural; T-Lymphocytes; Induced Pluripotent Stem Cells; Immunotherapy; Neoplasms
PubMed: 36599319
DOI: 10.1159/000528838 -
Nature Medicine Apr 2024Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to...
Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 10 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Glioma; T-Lymphocytes; Glioblastoma; Immunotherapy, Adoptive
PubMed: 38454126
DOI: 10.1038/s41591-024-02875-1 -
Journal For Immunotherapy of Cancer Apr 2023Immunotherapy has revolutionized the treatment of cancer. In particular, immune checkpoint blockade, bispecific antibodies, and adoptive T-cell transfer have yielded... (Review)
Review
Immunotherapy has revolutionized the treatment of cancer. In particular, immune checkpoint blockade, bispecific antibodies, and adoptive T-cell transfer have yielded unprecedented clinical results in hematological malignancies and solid cancers. While T cell-based immunotherapies have multiple mechanisms of action, their ultimate goal is achieving apoptosis of cancer cells. Unsurprisingly, apoptosis evasion is a key feature of cancer biology. Therefore, enhancing cancer cells' sensitivity to apoptosis represents a key strategy to improve clinical outcomes in cancer immunotherapy. Indeed, cancer cells are characterized by several intrinsic mechanisms to resist apoptosis, in addition to features to promote apoptosis in T cells and evade therapy. However, apoptosis is double-faced: when it occurs in T cells, it represents a critical mechanism of failure for immunotherapies. This review will summarize the recent efforts to enhance T cell-based immunotherapies by increasing apoptosis susceptibility in cancer cells and discuss the role of apoptosis in modulating the survival of cytotoxic T lymphocytes in the tumor microenvironment and potential strategies to overcome this issue.
Topics: Humans; Immunotherapy; Neoplasms; Immunotherapy, Adoptive; T-Lymphocytes, Cytotoxic; Apoptosis; Tumor Microenvironment
PubMed: 37055217
DOI: 10.1136/jitc-2022-005967 -
Blood Sep 2016The treatment of multiple myeloma has evolved significantly over the last decades from primarily alkylator-based chemotherapeutic agents with minimal efficacy to the... (Review)
Review
The treatment of multiple myeloma has evolved significantly over the last decades from primarily alkylator-based chemotherapeutic agents with minimal efficacy to the introduction of more effective agents including immune modulators and proteasome inhibitors, which have changed the landscape of therapy for this disease. We are now entering a new era that will increasingly integrate immunotherapy into standard treatment. This review discusses the current immune-based strategies currently approved, as well as various immune approaches being actively investigated including monoclonal antibodies, checkpoint inhibitors, vaccines, and adoptive T-cell therapies.
Topics: Antibodies, Monoclonal; Cancer Vaccines; Humans; Immune Tolerance; Immunotherapy; Immunotherapy, Adoptive; Multiple Myeloma; T-Lymphocytes
PubMed: 27506540
DOI: 10.1182/blood-2016-05-636357 -
American Journal of Hematology May 2019CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy has demonstrated impressive results in B-cell malignancies, and CAR-T cell therapies... (Review)
Review
CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy has demonstrated impressive results in B-cell malignancies, and CAR-T cell therapies targeting other antigens are in development for other cancers. Cytokine release syndrome (CRS) and neurotoxicity can be life-threatening in a subset of patients. The severity of CRS and neurotoxicity can be impacted by the disease burden, lymphodepletion regimen, and CAR-T cell dose. Tocilizumab and corticosteroids have been used to manage these toxicities, enabling CD19 CAR-T cells to be administered without obvious compromise in efficacy. Consensus criteria for grading and managing toxicities will facilitate the widespread application of this treatment modality.
Topics: Antigens, CD19; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Neurotoxicity Syndromes; Receptors, Antigen, T-Cell
PubMed: 30784102
DOI: 10.1002/ajh.25445