149P - Evaluation of HLA genotype as predictive biomarker for immunological and clinical responses upon vaccination with PolyPEPI1018 cancer vaccine against colorectal cancer

Background

HLA genes regulate immune responses. Cancer vaccines elicit immune responses in vaccinated subjects. Robust immune responses elicited by PolyPEPI1018 off-the-shelf peptide cancer vaccine are consistently associated with clinical benefit. We have investigated whether clinical outcome can be predicted based on the HLA genotype of MSS mCRC subjects, who participated in 3 clinical studies conducted with PolyPEPI1018 in combination with other agents^1,2,3.

Methods

Patients’ HLA class I genotype, vaccine antigen-specific CD8+ T cell responses (ELISpot) and clinical outcome (tumor responses by RECIST 1.1 and OS) were obtained from 3 studies involving PolyPEPI1018 (NCT03391232, NCT05130060, NCT05243862, n=44). Epitopes binding to autologous HLA-alleles were identified with our novel PEPI Test prediction tool and correlated with immunological and clinical responses.

Results

Epitopes restricted to >=3 HLA alleles of a person (PEPIs) elicited CD8+ T cell responses of higher magnitude than epitopes restricted to < 3 HLA alleles derived from the same antigen (n=9, p=0.034), despite no difference in the average predicted binding affinity of the epitopes (p=0.52). The precision for the PEPIs predicting the antigen-specific immune responses as determined by Area Under the Receiving Operating Curve (ROC AUC) was 0.66 (n=10, p=0.013), whereas for epitopes the AUC was 0.52. The post-treatment decrease in tumor burden was also dependent on the number of predicted PEPIs (AUC=0.67 [95%CI 0.51-0.83]; n=42). The risk ratio between the highest risk (PEPI < 2) and the lowest risk (PEPI > 4) for tumor increase was 2.21 comparing the top and bottom 25% of the PEPI distribution (p=0.044). Furthermore, patients with predicted PEPI ≥ 2 had longer overall survival than patients with PEPI < 2 (HR =0.28 [95%CI 0.07-1.17], n=15), treated with PolyPEPI1018 in combination with Lonsurf.

Conclusions

Patients complete HLA genotype is the link between the vaccine-elicited robust immune responses and treatment benefit. Based on these encouraging initial results further development of PolyPEPI1018 vaccine with companion diagnostic is warranted.

Clinical trial identification

NCT03391232, NCT05130060, NCT05243862.

Editorial acknowledgement

Legal entity responsible for the study

Treos Bio Ltd.

Funding

Treos Bio Ltd.

Disclosure

J. Hubbard: Financial Interests, Institutional, Advisory Board: Incyte, BeiGene; Financial Interests, Personal, Advisory Board: Bayer, Merck; Financial Interests, Institutional, Local PI: Boston Biomedical, Senhwa Biosciences, Bayer, Merck, Hutchison MediPharma, Seattle Genetics, Tovogene, TriOncology, Incyte, Pionyr, G1 Therapeutics, eFFECTOR Therapeutics, Roche; Financial Interests, Institutional, Coordinating PI: Taiho Pharmaceutical, TreoBio. L. Molnar: Financial Interests, Personal, Stocks/Shares: Treos Bio; Financial Interests, Personal, Full or part-time Employment: Treos Bio. J. Toth: Financial Interests, Personal, Full or part-time Employment, Bioinformatician: Treos Bio Zrt.; Financial Interests, Personal, Stocks/Shares: Teos Bio Limited. O. Lorincz: Financial Interests, Personal, Full or part-time Employment: Treos Bio; Financial Interests, Personal, Stocks/Shares: Treos Bio. Z. Csiszovszki: Financial Interests, Personal, Full or part-time Employment: Treos Bio Zrt; Financial Interests, Personal, Stocks/Shares: Treos Bio Ltd. E. Somogyi: Financial Interests, Personal, Full or part-time Employment, I am senior researcher at Treos Bio Zrt.: Treos Bio Zrt.; Financial Interests, Personal, Stocks/Shares, I hold shares at Treos Bio Ltd.: Treos Bio Ltd.. E.R. Toke: Financial Interests, Personal, Full or part-time Employment: Treos Bio Zrt; Financial Interests, Personal, Member of Board of Directors: Treos Bio Ltd; Financial Interests, Personal, Stocks/Shares: Treos Bio Ltd.