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Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs).

ABSTRACT: Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response.

SUBMITTER: Cassioli C

PROVIDER: S-EPMC9694822 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs).

Cassioli Chiara C Patrussi Laura L Valitutti Salvatore S Baldari Cosima T CT

International journal of molecular sciences 20221117 22

Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have uni ...[more]

PMID: 36430728

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Project description:Chimeric Antigen Receptor (CAR) immunotherapy utilizes genetically-engineered immune cells that express a unique cell surface receptor that combines tumor antigen specificity with immune cell activation. In recent clinical trials, the adoptive transfer of CAR-modified immune cells (including CAR-T and CAR-NK cells) into patients has been remarkably successful in treating multiple refractory blood cancers. To improve safety and efficacy, and expand potential applicability to other cancer types, CARs with different target specificities and sequence modifications are being developed and tested by many laboratories. Despite the overall progress in CAR immunotherapy, conventional tools to design and evaluate the efficacy and safety of CAR immunotherapies can be inaccurate, time-consuming, costly, and labor-intensive. Furthermore, existing tools cannot always determine how responsive individual patients will be to a particular CAR immunotherapy. Recent work in our laboratory suggests that the quality of the immunological synapse (IS) can accurately predict CAR-modified cell efficacy (and toxicity) that can correlate with clinical outcomes. Here we review current efforts to develop a Synapse Predicts Efficacy (SPE) system for easy, rapid and cost-effective evaluation of CAR-modified immune cell immunotherapy. Ultimately, we hypothesize the conceptual basis and clinical application of SPE will serve as an important parameter in evaluating CAR immunotherapy and significantly advance precision cancer immunotherapy. Video abstract Graphic abstract for manuscript CCAS-D-20-00136 by Liu, D., et al., 'The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy". The various branches of evaluating cancer immunotherapy metaphorically represented as a Rubik's cube. The development of a novel approach to predict the effectiveness of Chimeric Antigen Receptor (CAR)-modified cells by quantifying the quality of CAR IS will introduce a new parameter to the rapidly expanding field of cancer immunotherapy. Currently, no single parameter can predict the clinical outcome or efficacy of a specific type of CAR-modified cell. IS quality will serve as a quantifiable measure to evaluate CAR products and can be used in conjunction with other conventional parameters to form a composite clinical predictor. Much like a Rubik's cube has countless configurations, several methods and combinations of clinical metrics have arisen for evaluating the ability of a given immunotherapeutic strategy to treat cancer. The quality of IS depicting cancer immunotherapy is metaphorically expressed as a Rubik's cube. Each face/color represents one aspect of cancer therapy. Each grid in one face indicates one factor within that aspect of cancer therapy. For example, the green color represents the tumor microenvironment, and one out of the nine grids in the green color indicates suppressor cells (suppressors in green). Changes in one factor may completely alter the entire strategy of cancer therapy. However, the quality of IS (illuminated center red grid) makes the effectiveness of CAR immunotherapy predictable.

Project description:Owing to non-responsiveness of a high number of patients to the common melanoma therapies, seeking novel approaches seem as an unmet requirement. Chimeric antigen receptor (CAR) T cells were initially employed against recurrent or refractory B cell malignancies. However, advanced stages or pretreated patients have insufficient T cells (lymphopenia) amount for collection and clinical application. Additionally, this process is time-consuming and logistically cumbersome. Another limitation of this approach is toxicity and cytokine release syndrome (CRS) progress and neurotoxicity syndrome (NS). Natural killer (NK) cells are a versatile component of the innate immunity and have several advantages over T cells in the application for therapies such as availability, unique biological features, safety profile, cost effectiveness and higher tissue residence. Additionally, CAR NK cells do not develop Graft-versus-host disease (GvHD) and are independent of host HLA genotype. Notably, the NK cells number and activity is affected in the tumor microenvironment (TME), paving the way for developing novel approaches by enhancing their maturation and functionality. The CAR NK cells short lifespan is a double edge sword declining toxicity and reducing their persistence. Bispecific and Trispecific Killer Cell Engagers (BiKE and Trike, respectively) are emerging and promising immunotherapies for efficient antibody dependent cell cytotoxicity (ADCC). CAR NK cells have some limitations in terms of expanding and transducing NK cells from donors to achieve clinical response. Clinical trials are in scarcity regarding the CAR NK cell-based cancer therapies. The CAR NK cells short life span following irradiation before infusion limits their efficiency inhibiting their in vivo expansion. The CAR NK cells efficacy enhancement in terms of lifespan TME preparation and stability is a goal for melanoma treatment. Combination therapies using CAR NK cells and chemotherapy can also overcome therapy limitations.

Dataset Information

Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs).

Publications

Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs).

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