A phase 1 study of VAC85135, a neoantigen vaccine regimen targeting calreticulin and JAK2 mutations, in combination with ipilimumab in patients with myeloproliferative neoplasms

Abstract Disease-specific somatic mutations (mut) in calreticulin ( CALR ) and JAK2 ( JAK2V617F ) are drivers of myeloproliferative neoplasms (MPNs), causing generation of immunogenic peptide epitopes hypothesized to be vaccine-targetable neoantigens. VAC85135, a heterologous prime-boost vaccine regimen comprising adenoviral and vaccinia vectors encoding polypeptides specific to mutCALR and JAK2V617F , concurrent with anti-CTLA-4, ipilimumab, was investigated in a phase 1 study. Fourteen (myelofibrosis [MF], n = 10, essential thrombocythemia [ET], n = 4; mutCALR , n = 12, JAK2V617F , n = 2) patients were enrolled across three cohorts. A safety lead-in cohort (C0) received VAC85135 alone by intramuscular injection. Following acceptable tolerability, intramuscular VAC85135 was co-administered with intravenous ipilimumab: 1 mg/kg (C1) or 3 mg/kg (C2). Antigen-specific T-cell immune responses were analyzed by IFN-γ ELISpot. Clinical responses were evaluated per IWG-MRT-ELN criteria. Treatment-related adverse events were reported in 64.3% of patients; mostly Grade 1/2. Positive immune responses to mutCALR were observed post-vaccination in 5/14 (35.7%) patients. Immune response was maintained in one C0 patient over the treatment duration starting after dose 3; responses in four C1 patients were transient and observed after dose 7 in 2/4 patients. No patients had reduced mutCALR or JAK2V617F mutant allele burden at any post-vaccination timepoint. Consistent reductions in reticulin fibrosis were not observed in post-vaccination bone marrow biopsies. Best overall response was stable disease in nine patients with MF and no response in four patients with ET. The absence or delayed onset of immune response in most patients suggest VAC85135 was poorly immunogenic and unable to generate productive CALR or JAK2 neoantigen antitumor immunity. ClinicalTrials.gov identifier: NCT05444530.