Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer

J Clin Oncol. 2015 Apr 20;33(12):1325-33. doi: 10.1200/JCO.2014.57.4244. Epub 2015 Jan 12.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / adverse effects
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / adverse effects
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / therapy*
  • Combined Modality Therapy
  • Cyclophosphamide / administration & dosage*
  • Cyclophosphamide / adverse effects
  • Female
  • GPI-Linked Proteins / biosynthesis*
  • GPI-Linked Proteins / genetics
  • Humans
  • Listeria monocytogenes / genetics
  • Listeria monocytogenes / metabolism*
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / therapy*
  • Survival Rate
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Antineoplastic Agents, Alkylating
  • Cancer Vaccines
  • GPI-Linked Proteins
  • GVAX vaccine
  • Cyclophosphamide
  • mesothelin