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A Randomized Phase II Study: CRS207/GVAX plus Anti-PD-1 and Anti-CTLA4 Recruits Mesothelin- and mKRAS-Specific T
Katherine M Bever1, Amanda L Huff1, Ludmila Danilova1
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Cancer Immunology Research
|January 12, 2026
Summary
This study combined cancer vaccines (CRS-207, GVAX) with checkpoint inhibitors for pancreatic cancer, generating T-cell responses but facing barriers from myeloid cell enrichment.
Area of Science:
- Oncology
- Immunotherapy
- Vaccine Development
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has poor immunogenicity and high lethality, necessitating novel immunotherapeutic strategies.
- Previous research aimed to elicit clinical immune responses against PDAC using vaccines.
- Checkpoint inhibition is a key strategy in cancer immunotherapy.
Purpose of the Study:
- To evaluate the safety and efficacy of combining mesothelin-secreting listeria vaccine (CRS-207) and GM-CSF-secreting allogeneic whole-cell vaccine (GVAX) with checkpoint inhibitors (nivolumab, ipilimumab) in metastatic PDAC.
- To assess the impact of GVAX on the combination immunotherapy regimen.
- To investigate treatment-induced immune changes in the tumor microenvironment (TME).
Main Methods:
- Phase II, randomized study (NCT03190265) of metastatic PDAC patients progressing on chemotherapy.
- Treatment arms: CRS-207 with nivolumab and ipilimumab, with (Arm A) or without (Arm B) GVAX.
- Primary endpoint: Objective Response Rate (ORR); Secondary endpoint: Safety. Mass cytometry and T-cell receptor sequencing were used for immune analysis.
Main Results:
- Two partial responses (4% ORR) were observed, both in Arm B; no significant difference in ORR between arms.
- Grade ≥3 adverse events occurred in 68% of patients, with 33 events attributed to CRS-207.
- Treatment promoted T-cell memory and infiltration, expanding clones specific to mesothelin and mutant KRAS. Myeloid cell enrichment and high myeloid/Treg signatures correlated with poor responses.
Conclusions:
- The combination of GVAX/CRS-207 with nivolumab and ipilimumab successfully generates and expands T-cell clones specific to mesothelin and mutant KRAS in the PDAC TME.
- Immunotherapy-induced myeloid cell enrichment presents a significant barrier to achieving greater efficacy in PDAC.
- Further strategies are needed to overcome myeloid-mediated suppression for improved pancreatic cancer immunotherapy outcomes.
