Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer

Abstract

Purpose GVAX pancreas, granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes–expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Patients and Methods Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. Results A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Conclusion Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

Nanomedicine developments in the treatment of metastatic pancreatic cancer: focus on nanoliposomal irinotecan

“…21 Nevertheless, in a randomized Phase II trial in patients with chemorefractory metastatic pancreatic cancer, CRS-207, when combined with the cellular vaccine GVAX, significantly improved survival when compared to GVAX alone (median OS: 6.0 vs 3.4 months, HR =0.4477; P=0.0057), including in some patients with very prolonged disease stabilizations. 22 These results have led to successor trials comparing this vaccinebased strategy to chemotherapy, as well as evaluating it in combination with immune checkpoint blockade, in the second-and third-line settings.…”

Pancreatic cancer: treatment approaches and trends

“…Stable disease rate of 31% and 1-year survival rate of 24% are encouraging results. Furthermore, heterologous boost with Cy-GVAX and CRS-207 extended overall survival for pancreatic cancer patients with minimal related toxicities [90] [ Table 3]. …”

Phase I Study of DMOT4039A, an Antibody–Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer

“…Notwithstanding, with high frequency of expression in pancreatic and ovarian tumors, and expression limited to slowly dividing normal tissues with mesothelial cell lining (pleural, pericardial, and peritoneal surfaces), mesothelin is an attractive antigen target for antibody-based therapies coupled to cytotoxic agents. The target has been clinically validated, with antitumor activity demonstrated in various antimesothelin-derived antibody constructs, albeit with modest activity (12,13), and with a live-attenuated listeria vaccine expressing mesothelin 14,15).…”