Researchers from UCLA’s Department of Microbiology, Immunology, & Molecular Genetics (MIMG), and the department of Molecular and Medical Pharmacology have identified a set of tissue-specific antigens which have been used to isolate and characterize a group of novel T-cell receptors (TCRs) which target prostate cancer specifically. Furthermore, this platform and approach are readily adaptable to other cancer types.
BACKGROUND:
Adoptive T-cell transfer-based cancer immunotherapy has exhibited the capacity to induce a potent response to solid tumors in patients across several different cancer types. Adoptive cell therapies make use of T-cell’s natural cytotoxicity to target and kill cancer cells. One strategy to direct T-cells at cancer cells relies on the identification of T-cell receptors (TCRs) that specifically target peptide antigens displayed on major histocompatibility complexes (MHCs) on the surface of tumor cells. These TCRs are then engineered into T-cells to produce populations of therapeutic cells. It is therefore paramount that antigen targets that differentiate cancer-associated tissue from unrelated healthy cells are harnessed for the development of therapeutic TCRs. However, identification of effective antigen-TCR pairings is difficult, as productive targeting requires that the antigen be both sufficiently expressed and tissue specific to create a useful therapeutic window. TCRs directed at an antigen that is ubiquitously expressed by various tissues and organs suffer from “on-target off-tumor” toxicity and damage to healthy tissue. As a result, identification of antigen-TCR pairings that restrict targeting to one tissue type with high specificity is incredibly valuable for a clinical response with minimal side-effects.
INNOVATION:
UCLA researchers have used multiple immunopeptidomic approaches to identify a set of tissue-specific restricted peptides in the prostate. These peptides were then used to identify T-cell receptors (TCRs) that show high specificity for epitopes in these peptides when introduced to human peripheral blood mononuclear cells (PBMCs). In various assays, these modified PBMCs selectively targeted cells expressing the target epitope without affecting control non-epitope presenting cells. This tissue-specific antigen is predominantly expressed in the prostate. This make this TCR a perfect candidate for treatment of advanced-stage prostate cancer, where many patients have already undergone prostatectomies, and thus reducing “on-tumor off-target” toxicity. These epitopes and tissue-specific TCRs serve as a starting point for in-vivo experiments and further potential clinical development. This technology could be used in conjunction with other T-cell engineering/ affinity maturation strategies to make the engineered TCR T-cell even more potent.
POTENTIAL APPLICATIONS:
- Treatment of prostate cancer tumors
- Tissue specific localization
- Workflow can be used for other cancer types
- Advanced stage cancer therapy
ADVANTAGES:
- Tissue specific
- Increased immune response
- Highly selective for tumor cells
- Reduced “on-target off-tumor” toxicity
DEVELOPMENT-TO-DATE:
Antigen-TCR pairing has been identified which has a robust but specific response in various in-vitro assays and preliminary in-vivo tests against antigens that are presented on prostate cancer. Both the antigen and TCR have been characterized through various ‘omic’ and laboratory techniques.