A Randomized Phase II Study: CRS207/GVAX plus Anti-PD-1 and Anti-CTLA4 Recruits Mesothelin- and mKRAS-Specific T Cells into PDAC
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Published on: September 25, 2018
Katherine M Bever1, Amanda L Huff1, Ludmila Danilova1
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
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 (MSLN)-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-PD-1 (nivolumab) and anti-CTLA4 (ipilimumab) with (arm A) or without (arm B) GVAX. The primary endpoint was the objective response rate (ORR), and the secondary endpoint was safety. Fifty-seven patients received at least one dose of treatment, with two partial responses (4% ORR), in 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 MSLN and mutant KRAS within the tumor. Accompanying these antitumor T-cell responses was significant enrichment of myeloid cells. High myeloid and regulatory T-cell signatures correlated with poor responses. We conclude that GVAX/CRS-207 plus nivolumab and ipilimumab successfully generates and expands T-cell clones specific to MSLN and mutant KRAS within the PDAC TME, but immunotherapy-induced myeloid cell enrichment remains a barrier to greater efficacy. See related article by Sidiropoulos et al., p. 399.
Insights
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.
