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.

• Authors: Dung T Le, Andrea Wang-Gillam, Vincent Picozzi, Tim F Greten, Todd Crocenzi, Gregory Springett, Michael Morse, Herbert Zeh, Deirdre Cohen, Robert L Fine, Beth Onners, Jennifer N Uram, Daniel A Laheru, Eric R Lutz, Sara Solt, Aimee Luck Murphy, Justin Skoble, Ed Lemmens, John Grous, Thomas Dubensky Jr, Dirk G Brockstedt, Elizabeth M Jaffee
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 12 Pg. 1325-33 (Apr 20 2015) ISSN: 1527-7755 [Electronic] United States
• PMID: 25584002 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by American Society of Clinical Oncology.

Chemical References

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

Topics

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