Modi-1, anti-citrullinated neoepitope vaccine, alone and combined with checkpoint inhibitors in patients with head and neck, breast, renal, and ovarian cancers: ModiFy phase I/II basket clinical trial-Report after completion of monotherapy dose-finding

2566 Background: Stressful conditions in the tumor microenvironment induce autophagy, resulting in high levels of calcium in autophagosomes, in turn activating peptidylarginine deiminase enzymes; these convert arginine residues within polypeptides to citrulline and alter proteolytic cleavage. MHC-II presents these citrullinated peptides to CD4 + T cells. Modi-1 comprising three citrullinated, adjuvanted peptides targeting vimentin and enolase to inducing and expanding CD4 + T cells. At the tumor site the CD4 + T cells release proinflammatory cytokines including INFγ, further upregulating MHC class II. This enables presentation of endogenous citrullinated peptides on the tumor cells in a positive feed-forward loop. Methods: ModiFY is an open-label, multicohort, multicenter, adaptive Phase I/II basket trial for patients with unresectable Head and Neck Squamous Cell Carcinoma (SCCHN), Triple Negative Breast Cancer (TNBC), Renal Cell Carcinoma and High Grade Serous Ovarian Carcinoma (HGSOC). Patients are treated with Modi-1 alone or - if eligible for standard of care checkpoint inhibitor (CPI) monotherapy - Modi-1 + SoC CPI. The Modi-1 only expansion cohorts will recruit 16 patients per tumor type, Modi-1+CPI will recruit 21 patients per tumor type. Study objectives are safety, the breadth and strength of the cellular immune response, ORR, duration of response, PFS, and OS. Results: As of February 2023, the monotherapy dose-finding has completed. 3 patients received Mod1-1v (vimentin only) 80 µg/peptide and 3 patients received Modi-1 at 400 µg/peptide (vimentin + enolase peptides) as part of the monotherapy dose escalation. No DLTs were observed, triggering enrolment into the monotherapy expansion cohorts. 20 evaluable pts have received Modi-1v (3 pts Modi-1v 80 µg/peptide, 17 Modi-1 400 µg/peptide): 16 had HGSOC, 2 TNBC, 2 SCCHN with 53 doses received; 2 patients have been treated beyond 24 weeks. All patients had skin reactions consistent with a delayed-type hypersensitivity reaction at injection sites. Vaccinations have been well tolerated with 71 adverse reactions in 15 patients reported. All were Grade 1 or 2 except for four Grade 3 reactions in 3 patients (anemia, fatigue, and injection site reactions). There have been no SAEs. Elevation in anti-CCP antibodies has not been seen. In 13 response-evaluable patients, best overall response by RECIST v1.1 included 1 PR (SCCHN), 6 SD and 6 PD. The study is currently enrolling into the combination with checkpoint inhibition dose escalation cohorts and the monotherapy expansion cohorts. Conclusions: Modi-1 is well tolerated, and the early monotherapy efficacy data are encouraging. Safety and early efficacy data are supportive of further development of combination with CPI. Clinical trial information: NCT05329532 .