Cancer Immunol Res. 2026 Jan 12. doi: 10.1158/2326-6066.CIR-25-0545. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and has poor immunogenicity, warranting the use of vaccines to guide and recruit the immune response. Building on prior efforts to achieve clinical immunotherapeutic responses against PDAC, we conducted a phase II study (NCT03190265) that combined attenuated mesothelin-secreting listeria vaccine (CRS-207) and GM-CSF-secreting allogeneic whole-cell vaccine (GVAX) along with checkpoint inhibition. Patients with metastatic PDAC who progressed on chemotherapy were enrolled in one of two treatment arms in a randomized fashion. CRS-207 was given with anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) with (Arm A) or without (Arm B) GVAX. Primary endpoint was objective response rate (ORR) and the secondary endpoint was safety. 57 patients received at least one dose of treatment, with 2 partial responses (4% ORR), both Arm B. The response rates were not significantly different between the two arms. Related grade ≥3 adverse events were seen in 39 (68%) patients, including 33 events attributed to CRS-207. Mass cytometry analysis of serially obtained biospecimens demonstrated treatment-induced promotion of T-cell memory and infiltration into the tumor microenvironment (TME). Peptide-specific T-cell expansions in vitro followed by T-cell receptor sequencing revealed clones specific to mesothelin and mutant KRAS within the tumor. Accompanying these antitumor T-cell responses was significant enrichment of myeloid cells. High myeloid and Treg signatures correlated with poor responses. We conclude that GVAX/CRS-207 plus nivolumab and ipilimumab successfully generates and expands T-cell clones specific to mesothelin and mutant KRAS within the PDAC TME but immunotherapy-induced myeloid-cell enrichment remains a barrier to greater efficacy.

PMID:41524570 | DOI:10.1158/2326-6066.CIR-25-0545