Journal of Clinical and Cellular Immunology
Open Access

Tumor Antigens as Targets for Chimeric Antigen Receptor (CAR) T-Cell Therapy

Elizabeth Jones^{* *}Correspondence: Elizabeth Jones, Department of Oncoimmunology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, Email:

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Description

Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment for certain types of cancers, particularly hematological malignancies. This innovative approach utilizes the power of the immune system by genetically modifying T cells to express receptors that specifically recognize tumor antigens. Tumor antigens and their role in CAR T-cell therapy is necessary for optimizing treatment outcomes and expanding its application to a broader range of malignancies.

Tumor antigens are substances produced by tumor cells that can trigger an immune response and are classified into two main categories. Tumor-Specific Antigens (TSAs) are unique to cancer cells and arise from mutations in tumor Deoxyribonucleic Acid (DNA), meaning they are typically not present in normal cells, making them ideal targets for immunotherapy. Examples of TSAs include mutated proteins resulting from oncogenes or tumor suppressor genes [1].

On the other hand, Tumor-Associated Antigens (TAAs) are proteins that are overexpressed in tumor cells compared to normal cells, although they can also be found in healthy tissues. Common examples of TAAs include Human Epidermal Growth Factor Receptor 2 (HER2) in breast cancer and Prostate-Specific Antigen (PSA) in prostate cancer. While TAAs are less specific than TSAs, they still represent valuable targets for CAR T-cell therapy.

Mechanism of CAR T-cell therapy

CAR T-cell therapy involves several steps:

T-cell collection: T cells are harvested from a patient’s blood.

Genetic modification: The collected T cells are genetically engineered in the laboratory to express CARs, which are synthetic receptors designed to recognize specific tumor antigens [2].

Expansion: The modified T cells are expanded in culture to produce a sufficient quantity for infusion.

Infusion: The CAR T cells are infused back into the patient, where they seek out and destroy cancer cells expressing the target antigen.

Persistence and memory: Ideally, CAR T cells remain in the patient’s body, providing long-term surveillance against tumor recurrence.

Identifying target antigens

The selection of appropriate tumor antigens is essential for the success of CAR T-cell therapy. Factors to consider include:

Specificity: The target antigen should be primarily expressed on tumor cells to minimize damage to healthy tissues. This is particularly important for TAAs, where shared expression in normal cells can lead to on-target, off-tumor toxicity [3].

Expression levels: High expression of the target antigen on tumor cells is preferred to enhance the efficacy of CAR T cells.

Immunogenicity: The antigen should be capable of eliciting a robust immune response. This is especially relevant for TSAs, which can generate strong T cell activation [4].

Challenges in targeting tumor antigens

While targeting tumor antigens has great potential, several challenges remain:

Heterogeneity of tumors: Tumors can exhibit significant heterogeneity, with variations in antigen expression between different cells within the same tumor or between tumors in different patients. This diversity can lead to incomplete responses, as some tumor cells may not express the target antigen [5].

Antigen loss or downregulation: Some tumors can evade CAR T-cell detection by losing expression of the targeted antigen. This phenomenon is often observed in solid tumors and can lead to treatment resistance.

T cell exhaustion: CAR T cells can become exhausted in the tumor microenvironment, where high levels of inhibitory signals such as Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) can limit their effectiveness. Overcoming this exhaustion is necessary for sustained therapeutic activity.

Toxicity: Targeting TAAs can lead to off-tumor effects if the antigens are also expressed in normal tissues. Careful antigen selection and engineering of CARs can help mitigate this risk.

Innovations in CAR T-cell therapy

To address the challenges associated with tumor antigen targeting, several innovative strategies are being explored:

Dual-target CARs: CARs that target two different antigens simultaneously may improve efficacy and reduce the likelihood of tumor escape due to antigen loss.

Universal CAR T cells: These are engineered T cells that can be directed against multiple tumor antigens, potentially broadening their application across various malignancies.

Armored CARs: Modifications that enhance the persistence and activity of CAR T cells in the suppressive tumor microenvironment, such as incorporating costimulatory signals, are under investigation.

Bi-specific T cell Engagers (BiTEs): These molecules can engage T cells and target tumor cells by binding to two different antigens, enhancing T cell activation and cytotoxicity [6].

Future directions

The field of CAR T-cell therapy is rapidly evolving, with ongoing research aimed at improving efficacy and expanding its applicability to solid tumors. As knowledge of tumor antigens deepens, advancements in the design of CAR T cells can be expected to overcome current limitations.

Exploration of novel antigens: Continued study into the tumor genome will help identify new TSAs and TAAs that can serve as targets for CAR T-cell therapy.

Combination therapies: Combining CAR T-cell therapy with other treatment modalities, such as immune checkpoint inhibitors or traditional therapies, may enhance overall effectiveness and help overcome resistance.

Personalized approaches: Customizing CAR T-cell therapy to individual patients based on their unique tumor antigen profiles is expected to improve treatment outcomes.

Conclusion

Tumor antigens play an important role in the efficacy of CAR T-cell therapy, serving as the guiding targets for engineered T cells focused on eliminating cancer. Despite the challenges associated with tumor heterogeneity and immune evasion, ongoing innovations in CAR technology and a deeper knowledge of tumor biology are leading for more effective and personalized cancer treatments. As this field advances, CAR T-cell therapy has the potential to transform cancer therapy, offering possibilities to patients facing challenging malignancies.

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