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Updated: Mar 23, 2026
In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Molecular Pathways: Breaking the Epithelial Cancer Barrier for Chimeric Antigen Receptor and T-cell Receptor Gene
1Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, Maryland. Hinrichs@nih.gov.
Abstract:
Adoptive transfer of T cells genetically engineered to express a tumor-targeting chimeric antigen receptor (CAR) or T-cell receptor (TCR) can mediate cancer regression in some patients. CARs are synthetic single-chain proteins that use antibody domains to target cell surface antigens. TCRs are natural heterodimeric proteins that can target intracellular antigens through recognition of peptides bound to human leukocyte antigens. CARs have shown promise in B-cell malignancies and TCRs in melanoma, but neither approach has achieved clear success in an epithelial cancer. Treatment of epithelial cancers may be particularly challenging because of a paucity of target antigens expressed by carcinomas and not by important healthy tissues. In addition, epithelial cancers may be protected by inhibitory ligands and soluble factors in the tumor microenvironment. One strategy to overcome these negative regulators is to modulate expression of T-cell genes to enhance intrinsic T-cell function. Programmable nucleases, which can suppress inhibitory genes, and inducible gene expression systems, which can enhance stimulatory genes, are entering clinical testing. Other work is delineating whether control of genes for immune checkpoint receptors (e.g.,PDCD1, CTLA4) and cytokine and TCR signaling regulators (e.g.,CBLB, CISH, IL12, IL15) can increase the antitumor activity of therapeutic T cells.
Insights
Genetically engineered T cells, using chimeric antigen receptors (CARs) or T-cell receptors (TCRs), show promise for cancer treatment. Enhancing T-cell function through gene modulation may overcome challenges in treating epithelial cancers.
Area of Science:
- Immunology
- Oncology
- Genetic Engineering
Background:
- Adoptive T-cell therapy with chimeric antigen receptors (CARs) and T-cell receptors (TCRs) has shown success in certain cancers.
- Epithelial cancers present unique challenges due to limited tumor-specific antigens and an immunosuppressive tumor microenvironment.
- Existing CAR and TCR therapies have not yet achieved significant success in epithelial cancers.
Purpose of the Study:
- To explore strategies for enhancing T-cell function to improve adoptive T-cell therapy efficacy.
- To investigate methods for overcoming the challenges associated with treating epithelial cancers.
Main Methods:
- Engineering T cells with CARs targeting cell surface antigens or TCRs targeting intracellular antigens.
- Utilizing programmable nucleases to suppress inhibitory genes in T cells.
- Employing inducible gene expression systems to enhance stimulatory genes in T cells.
- Investigating the modulation of immune checkpoint receptors (e.g., PDCD1, CTLA4) and signaling regulators (e.g., CBLB, CISH, IL12, IL15).
Main Results:
- CARs are effective for B-cell malignancies, while TCRs show promise in melanoma.
- Epithelial cancers often lack suitable target antigens and possess immunosuppressive microenvironments.
- Gene modulation strategies, including nuclease and inducible systems, are being developed to enhance T-cell antitumor activity.
Conclusions:
- Enhancing T-cell intrinsic function through genetic engineering is a promising strategy to overcome limitations in treating epithelial cancers.
- Modulating genes related to immune checkpoints and signaling pathways can potentially increase the antitumor activity of therapeutic T cells.
- Further research into gene modulation techniques is crucial for advancing adoptive T-cell therapy for epithelial malignancies.
