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Finding the Keys to the CAR: Identifying Novel Target Antigens for T Cell Redirection Immunotherapies
Rebecca C Abbott1, Ryan S Cross1, Misty R Jenkins1,2,3
1Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Abstract:
Oncology immunotherapy has been a significant advancement in cancer treatment and involves harnessing and redirecting a patient's immune response towards their own tumour. Specific recognition and elimination of tumour cells was first proposed over a century ago with Paul Erlich's 'magic bullet' theory of therapy. In the past decades, targeting cancer antigens by redirecting T cells with antibodies using either bispecific T cell engagers (BiTEs) or chimeric antigen receptor (CAR) T cell therapy has achieved impressive clinical responses. Despite recent successes in haematological cancers, linked to a high and uniformly expressed CD19 antigen, the efficacy of T cell therapies in solid cancers has been disappointing, in part due to antigen escape. Targeting heterogeneous solid tumours with T cell therapies will require the identification of novel tumour specific targets. These targets can be found among a range of cell-surface expressed antigens, including proteins, glycolipids or carbohydrates. In this review, we will introduce the current tumour target antigen classification, outline existing approaches to discover novel tumour target antigens and discuss considerations for future design of antibodies with a focus on their use in CAR T cells.
Insights
Immunotherapy advances cancer treatment by redirecting immune responses. Identifying novel tumor-specific targets is crucial for improving T cell therapies in solid tumors, overcoming antigen escape.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Cancer immunotherapy harnesses the patient's immune system to fight tumors.
- T cell therapies, like bispecific T cell engagers (BiTEs) and chimeric antigen receptor (CAR) T cells, show promise but face challenges in solid tumors.
- Antigen escape limits the efficacy of current T cell therapies in solid cancers.
Purpose of the Study:
- To review current classifications of tumor target antigens.
- To outline methods for discovering novel tumor-specific targets.
- To discuss future antibody design considerations for CAR T cell therapy.
Main Methods:
- Literature review of tumor target antigen classification.
- Analysis of existing approaches for novel tumor antigen discovery.
- Discussion of antibody design principles for CAR T cells.
Main Results:
- Current T cell therapies are highly effective in hematological cancers due to uniform antigen expression (e.g., CD19).
- Solid tumors present challenges due to heterogeneity and antigen escape, limiting T cell therapy efficacy.
- Novel tumor-specific targets, including cell-surface proteins, glycolipids, and carbohydrates, are needed.
Conclusions:
- Advancing T cell therapies for solid tumors requires identifying new, specific targets.
- Future strategies should focus on discovering and validating novel antigens and optimizing antibody design for CAR T cells.
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