1422 Th1-specific TROP2 vaccine (AST-07X) elicits strong antigen-specific T cell responsesin vitro

Background

Th-Vac^® discovery platform, consists of module 1 (Immunoinformatics-based in-silico) and module 2 (in-vitro and vaccine efficacy evaluation) under the comprehensive immunologic algorithms, is aimed to identify antigen-specific MHC class II epitopes for CD4⁺ T cell with optimal binding affinity and promiscuity across multiple alleles. In a therapeutic cancer area, Th1-specific epitopes prediction followed by cancer vaccine discovery is fully applicable.^1–3 Therefore, an immunological mode of action of cancer vaccine powered by Th-Vac^® discovery platform is to generate the inflammatory T-cell immunity (type 1 immunity) against tumor antigens with enough potency to overcome either the absence of a T-cell immune response to the tumor or a preexisting immune tolerant response which tends to be the immune-suppressing (type 2 immunity) phenomenon. TROP2 protein is a transmembrane glycoprotein encoded by the Tacstd2 gene. It is known to be overexpressed on the surface of various epithelial cancer cells, including prostate cancer, colorectal cancer, pancreatic cancer, and ovarian cancer, although the role of TROP2 protein in cancer cell growth and proliferation is not well understood.⁴ In this study, Th1-specific TROP2 epitopes were precisely identified via module 1 and 2 of Th-Vac^® discovery platform.

Methods

MHC class II binding epitope predictions were conducted thru engaging common human MHC class II alleles in module 1 of Th-Vac^® discovery platform, and MHC class II-specific peptide sequences (up to 15 mers) were initially selected based on the rank order of the predicted binding affinity which are representing potential immunogenic hot spots to MHC class II. Each peptides were synthesized to be stepping into in-vitro immunologic assessment (module 2 of Th-Vac^® discovery platform). Th1-specific immunologic response was evaluated with ELISpot and/or FACS analysis.

Results

In a module 1 of Th-Vac^® discovery platform, 10 sequences (consists of 15 mers) were finally predicted as potential epitopes that have a high-affinity to MHC class II. In module 2 (2a for in-vitro and 2b for in-vivo immunologic evaluation), four epitopes out of 10 epitopes showed only strong Th1 immune responses without type 2 immunity in both ELISpot and FACS analysis.

Conclusions

TROP2 epitopes that were identified in the Th-Vac^® discovery platform has been developed as a promising ‘off-the-shelf’ type Th1-specific therapeutic cancer vaccine (AST-07X). Additionally, the Th-Vac^® platform were fully validated in terms of performance and its application would be expanded beyond a cancer vaccine.

References

Watt WC, Cecil DL, Disis ML. Selection of epitopes from self-antigens for eliciting Th2 or Th1 activity in the treatment of autoimmune disease or cancer. Semin Immunopathol. 2017 Apr;39(3):245–253. Disis ML, Watt WC, Cecil DL. Th1 epitope selection for clinically effective cancer vaccines. Oncoimmunology. 2014 Dec 13;3(9):e954971. Park KH, Gad E, Goodell V, Dang Y, Wild T, Higgins D, Fintak P, Childs J, Dela Rosa C, Disis ML. Insulin-like growth factor-binding protein-2 is a target for the immunomodulation of breast cancer. Cancer Res. 2008 Oct 15;68(20):8400–9 Shvartsur A, Bonaavida B, Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes & Cancer, 2015;6(3–4).