Generation of frameshift-mutated TGFβR2-specific T cells in healthy subjects following administration with cancer vaccine candidate FMPV-1/GM-CSF in a phase 1 study

Abstract

FMPV-1 is a component of FMPV-3, an investigational cancer-specific vaccine and being developed to activate anti-cancer T cell responses targeting frameshift mutations of MSI-H cancers. FMPV-1 is designed to activate T cell responses against transforming growth factor β receptor 2 (TGFβR2) frameshift mutation. Microsatellite instability high (MSI-H) gastrointestinal cancers frequently harbour TGFβR2 frameshift mutations. This first-in-human, phase 1, single centre, open-label study included 16 healthy male subjects who received FMPV-1 (0.15 mg/injection) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.03 mg/injection) as two separate, co-located, injections on Days 1, 8, 15, 29 and 43. All subjects were followed to Day 365. A FMPV-1-specific delayed type hypersensitivity (DTH) skin reactivity test was performed with FMPV-1 (without GM-CSF) on Days 1, 29 and 43 with assessment after 2 days. All subjects were DTH negative at baseline, 8/16 were positive on Day 31 and 15/16 were positive on Day 45. Furthermore, the FMPV-1/GM-CSF induced frameshift mutant TGFβR2-specific T cells after the short vaccination period, and specific T cells were still detectable after 6 and 12 months indicating induction of frameshift mutant TGFβR2-specific T memory cells. Adverse events were limited to mild injection site reactions with no evidence of related systemic signs or symptoms. No other clinically important changes to vital signs, electrocardiograms, haematological, coagulation or laboratory measures related to treatment were observed. FMPV-1/GM-CSF was well tolerated and generated vaccine-specific T cell immune responses in healthy subjects. These findings support clinical studies in patients with, or at risk of, cancers carrying TGFβR2 frameshift mutations.Clinical trial identification: ClinicalTrials.gov: NCT05238558. EudraCT: 2020-004363-80.

Keywords: GM-CSF; Immune response; Immunotherapy; Lynch syndrome; Peptide vaccine; TGFβR2.

Fig. 1

Study scheme

Fig. 2

Delayed type hypersensitivity (DTH) reactions following FMPV-1 challenge. DTH reactions were measured 48 h after ID injections with FMPV-1 peptide only. A DTH positive subjects at Day 3, Day 31, Day 45 (all n = 16) and Day 184 (n = 7). B Mean diameter of DTH reactions (mm ± SD) in evaluable subjects at Day 31 and Day 45 (n = 16) and at Day 184 (n = 7). C. Example of DTH reaction in a subject at Day 45. D Example of DTH reaction in a subject at Day 184 indicating generation of T memory cells

Fig. 3

T cell proliferation against FMPV-1 peptide in pre- and post-vaccination blood samples. A The strongest post-vaccination T cell responses detected against the FMPV-1 peptide up to Day 80 for each subject. B Post-vaccination T cell responses against the FMPV-1 peptide at Day 182 and Day 365 for each subject. Stimulation Index (SI) is plotted as mean of triplicates ± SD, SI ≥ 2 was considered immune response. All results with T cell count at Day 12–14 < 5 × 10⁴/well and the SI value of SEC 3 stimulated cells < 2 were excluded from the final analysis