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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Mechanisms of antigen-dependent resistance to chimeric antigen receptor (CAR)-T cell therapies
Fatemeh Nasiri1,2, Pouya Safarzadeh Kozani3,4, Faeze Salem5
1Department of Internal Medicine, College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Abstract:
Cancer immunotherapy has reshaped the landscape of cancer treatment over the past decades. Genetic manipulation of T cells to express synthetic receptors, known as chimeric antigen receptors (CAR), has led to the creation of tremendous commercial and therapeutic success for the treatment of certain hematologic malignancies. However, since the engagement of CAR-T cells with their respective antigens is solely what triggers their cytotoxic reactions against target cells, the slightest changes to the availability and/or structure of the target antigen often result in the incapacitation of CAR-T cells to enforce tumoricidal responses. This results in the resistance of tumor cells to a particular CAR-T cell therapy that requires meticulous heeding to sustain remissions in cancer patients. In this review, we highlight the antigen-dependent resistance mechanisms by which tumor cells dodge being recognized and targeted by CAR-T cells. Moreover, since substituting the target antigen is the most potent strategy for overcoming antigen-dependent disease relapse, we tend to highlight the current status of some target antigens that might be considered suitable alternatives to the currently available antigens in various cancers. We also propose target antigens whose targeting might reduce the off-tumor adverse events of CAR-T cells in certain malignancies.
Insights
CAR-T cell therapy faces resistance when tumors alter target antigens. This review explores antigen-dependent resistance mechanisms and discusses alternative antigens to improve efficacy and reduce side effects.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment, particularly for hematologic malignancies.
- CAR-T cell efficacy relies on the specific recognition of target antigens on cancer cells.
- Tumor cells can develop resistance by altering target antigen expression or structure, limiting CAR-T cell effectiveness.
Purpose of the Study:
- To review antigen-dependent resistance mechanisms employed by tumor cells against CAR-T cell therapy.
- To discuss alternative target antigens for overcoming resistance and improving therapeutic outcomes.
- To identify potential target antigens that could minimize off-tumor adverse events.
Main Methods:
- Literature review of studies on CAR-T cell therapy resistance mechanisms.
- Analysis of current research on alternative antigen targets in various cancers.
- Exploration of strategies to mitigate CAR-T cell-related toxicities.
Main Results:
- Identified key antigen-dependent mechanisms enabling tumor cells to evade CAR-T cell recognition and destruction.
- Highlighted promising alternative antigen targets currently under investigation for various malignancies.
- Proposed novel antigen targets that may enhance CAR-T cell specificity and safety.
Conclusions:
- Antigen escape is a significant challenge in CAR-T cell therapy, necessitating the exploration of new therapeutic strategies.
- Identifying and validating alternative antigens is crucial for overcoming treatment resistance and improving long-term patient remission.
- Strategic selection of target antigens holds the potential to enhance CAR-T cell therapy efficacy while reducing treatment-related toxicities.
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