A big STEP (Simultaneous Tumor and Effector Profiling) forward in the battle against chimeric antigen receptor (CAR) T-cell therapy resistance.
Ontology highlight
ABSTRACT:
SUBMITTER: Sondhi AK
PROVIDER: S-EPMC10643940 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
Publications
A big STEP (Simultaneous Tumor and Effector Profiling) forward in the battle against chimeric antigen receptor (CAR) T-cell therapy resistance.
Sondhi Anya K AK Risso Carla Barrientos CB Taylor Justin J
Translational cancer research 20231010 10
Similar Datasets
Project description:Despite the availability of an increasing number of targeted therapeutics and wider use of allogeneic hematopoietic stem cell transplantation, many patients with acute myeloid leukemia (AML) ultimately succumb to this disease. Given their remarkable efficacy in B-acute lymphoblastic leukemia and other CD19-expressing B cell malignancies, there is hope adoptive cellular transfer, particularly chimeric antigen receptor (CAR)-modified immune effector cell (IEC) therapies, may afford a novel, potent immune-based approach for the treatment of AML that complements or replaces existing ones and improves cure rates. However, it is unclear how best to translate the success of these therapies from B cell malignancies, where use of highly potent immunotherapies is facilitated by identified target antigens with near ubiquitous expression on malignant cells and non-fatal consequences from "on-target, off-tumor cell" toxicities. Herein, we review the current status of CAR-modified IEC therapies for AML, with considerations regarding suitable, relatively leukemia-restricted target antigens, expected toxicities, and interactions of the engineered cells with a profoundly immunosuppressive tumor microenvironment that restricts their therapeutic efficacy. With these challenges in mind, we will discuss possible strategies to improve the cells' potency as well as their therapeutic window for optimal clinical use in AML.
| S-EPMC7761730 | biostudies-literature
Project description:Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient's own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.
| S-EPMC7226583 | biostudies-literature
Project description:Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy. Inefficient T cell trafficking, immunosuppressive tumor microenvironment, suboptimal antigen recognition specificity, and lack of safety control are currently considered as the main obstacles in solid tumor CAR-T therapy. Here, we reviewed the solid tumor CAR-T clinical trials, emphasizing the studies with published results. We further discussed the challenges that CAR-T is facing for solid tumor treatment and proposed potential strategies to improve the efficacy of CAR-T as promising immunotherapy.
| S-EPMC5809840 | biostudies-literature
Project description: Not available
| S-EPMC8813057 | biostudies-literature
Project description:Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy.
| S-EPMC7865527 | biostudies-literature
Project description:Human T cells isolated from healthy donors were transduced with non-tonically signaling CARs or tonically signaling CARs, each with CD28z or 4-1BB costimulatory domains Human T cells isolated from healthy donors were transduced with non-tonically signaling CARs or tonically signaling CARs, each with CD28z or 4-1BB costimulatory domains
2015-04-09 | E-GEOD-65856 | biostudies-arrayexpress
Project description:Genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) are becoming increasingly important in the treatment of hematologic malignancies and are also intensively being investigated for other diseases such as autoimmune disorders and HIV. Current CAR T cell therapies predominantly use viral transduction methods which, despite their efficacy, raise safety concerns related to genomic integration and potentially associated malignancies as well as labor- and cost-intensive manufacturing. Therefore, non-viral gene transfer methods, especially mRNA-based approaches, have attracted research interest due to their transient modification and enhanced safety profile. In this study, the optimization of CAR-mRNA for T cell applications is investigated, focusing on the impact of mRNA modifications, in vitro transcription protocols, and purification techniques on the translation efficiency and immunogenicity of mRNA. Furthermore, the refined CAR-mRNA was used to generate transient CAR T cells from acute myeloid leukemia patient samples, demonstrating efficacy in vitro and proof-of-concept for clinically relevant settings. These results highlight the potential of optimized mRNA to produce transient and safe CAR T cells.
| S-EPMC11818003 | biostudies-literature
Project description:Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor's individual components-scFv, spacer domain, and costimulatory domains-and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.
| S-EPMC6470706 | biostudies-literature
Project description:IntroductionChimeric antigen receptors (CARs) usually combine the antigen binding site of a monoclonal antibody with the signal activating machinery of a T cell, freeing antigen recognition from MHC restriction and thus breaking one of the barriers to more widespread application of cellular therapy. Similar to treatment strategies employing monoclonal antibodies, T cells expressing CARs are highly targeted, but additionally offer the potential benefits of active trafficking to tumor sites, in vivo expansion and long-term persistence. Furthermore, gene transfer allows the introduction of countermeasures to tumor immune evasion and of safety mechanisms.Areas coveredThe basic structure of so-called first and later generation CARs and their potential advantages over other immune therapy systems. How these molecules can be grafted into immune cells (including retroviral and non-retroviral transduction methods) and strategies to improve the in vivo persistence and function of immune cells expressing CARs. Examples of tumor-associated antigens that have been targeted in preclinical models and clinical experience with these modified cells. Safety issues surrounding CAR gene transfer into T cells and potential solutions to them.Expert opinionBecause of recent advances in immunology, genetics and cell processing, CAR-modified T cells will likely play an increasing role in the cellular therapy of cancer, chronic infections and autoimmune disorders.
| S-EPMC3107373 | biostudies-literature
Project description: Not available
| S-EPMC5391777 | biostudies-literature