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

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

Author information

1
Dung T. Le, Beth Onners, Jennifer N. Uram, Daniel A. Laheru, Eric R. Lutz, Sara Solt, and Elizabeth M. Jaffee, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore; Tim F. Greten, National Cancer Institute, Bethesda, MD; Andrea Wang-Gillam, Siteman Cancer Center, Washington University, St Louis, MO; Vincent Picozzi, Virginia Mason Medical Center, Seattle, WA; Todd Crocenzi, Providence Portland Medical Center, Portland, OR; Gregory Springett, Moffitt Cancer Center, Tampa, FL; Michael Morse, Duke University Medical Center, Durham, NC; Herbert Zeh, University of Pittsburgh, Pittsburgh, PA; Deirdre Cohen, New York University Langone Medical Center; Robert L. Fine, Columbia University Medical Center, New York, NY; and Aimee Luck Murphy, Justin Skoble, Ed Lemmens, John Grous, Thomas Dubensky Jr, and Dirk G. Brockstedt, Aduro BioTech, Berkeley, CA. dle2@jhmi.edu.
2
Dung T. Le, Beth Onners, Jennifer N. Uram, Daniel A. Laheru, Eric R. Lutz, Sara Solt, and Elizabeth M. Jaffee, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore; Tim F. Greten, National Cancer Institute, Bethesda, MD; Andrea Wang-Gillam, Siteman Cancer Center, Washington University, St Louis, MO; Vincent Picozzi, Virginia Mason Medical Center, Seattle, WA; Todd Crocenzi, Providence Portland Medical Center, Portland, OR; Gregory Springett, Moffitt Cancer Center, Tampa, FL; Michael Morse, Duke University Medical Center, Durham, NC; Herbert Zeh, University of Pittsburgh, Pittsburgh, PA; Deirdre Cohen, New York University Langone Medical Center; Robert L. Fine, Columbia University Medical Center, New York, NY; and Aimee Luck Murphy, Justin Skoble, Ed Lemmens, John Grous, Thomas Dubensky Jr, and Dirk G. Brockstedt, Aduro BioTech, Berkeley, CA.

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.

PMID:
25584002
PMCID:
PMC4397277
DOI:
10.1200/JCO.2014.57.4244
[Indexed for MEDLINE]
Free PMC Article

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