138P - Generation of frameshift mutated TGF_R2-specific T cells in healthy subjects following administration with cancer vaccine candidate FMPV-1/GM-CSF

Background

Generation of specific and durable T cell response is the basis of antigen targeted cancer vaccine strategies. A study in healthy male subjects conducted over a one-year period investigated the generation of antigen specific T cell responses from a peptide vaccine FMPV-1, targeting frameshift mutated (mut) transforming growth factor receptor 2 (TGFβR2), commonly occurring in cancers with microsatellite instability (MSI-H). Granulocyte macrophage colony stimulating factor (GM-CSF) was used as adjuvant.

Methods

An open label study was conducted in 16 healthy male subjects who received intradermal FMPV-1 (0.15 mg/injection) preceded by GM-CSF (0.03mg/injection) on Days 1, 8, 16, 29 and 43. Immune responses were assessed by in vivo delayed type hypersensitivity (DTH) in all subjects on Days 1, 29 and 43 and in 7 subjects after 6 months, and in vitro assessment of induced FMPV-1 antigen specific T cells at Days 1, 57, 80, 6 months and 12 months, with Stimulation Index (SI) values ≥ 2 considered positive. Plasma samples were assayed for the presence of mut (A9) TGFβR2 circulating cell-free DNA (cfDNA) fragments and wildtype (wt) (A10) TGFβR2 cfDNA fragments. Subjects were assessed for safety and tolerability.

Results

None of the 16 subjects had a positive DTH before vaccination. After 3 and 4 vaccinations, 8/16 and 15/16 subjects had a positive DTH response respectively. At 6 months 5/7 subjects still had a positive DTH response. FMPV-1 antigen-specific T cells were detected shortly after the vaccination period and at 6 and 12 months. Neither mut nor wt TGFβR2 cfDNA fragments were detected in any subject. Vaccination with FMPV-1/GM-CSF was well tolerated out to 1 year following initial dosing.

Conclusions

The FMPV-1 peptide vaccine is immunogenic and induces frameshift mutant TGFβR2 specific T cells after a short vaccination period in healthy subjects. This provides a rationale for FMPV-1 treatment of MSI-H cancer patients in combination with immune checkpoint inhibitors. With the favourable safety profile and ability to induce frameshift mut TGFβR2 specific memory T cells, FMPV-1/GM-CSF may play an important role in both therapeutic and prophylactic settings of cancer.

Clinical trial identification

EudraCT 2020-004363-80.

Legal entity responsible for the study

Quotient Sciences.

Funding

Hubro Therapeutics AS.

Disclosure

S.J. Arbe-Barnes: Financial Interests, Personal, Full or part-time Employment: Hubro Therapeutics AS. J.A. Eriksen: Financial Interests, Personal and Institutional, Stocks/Shares: Hubro Therapeutics AS; Financial Interests, Personal, Officer: Hubro Therapeutics AS. B. Iverson, H. Kvalheim, R.M. Miller, K. Risberg Handeland: Financial Interests, Institutional, Full or part-time Employment: Hubro Therapeutics AS. N. Singh: Other, Institutional, Local PI: Quotient Sciences. All other authors have declared no conflicts of interest.