Dung T. Le1, Andrea Wang‐Gillam1, Vincent J. Picozzi1, Tim F. Greten1, Todd S. Crocenzi1, Gregory M. Springett1, Michael A. Morse1, Herbert J. Zeh1, Deirdre Jill Cohen1, Robert L. Fine1, Beth Onners1, Jennifer N. Uram1, Daniel A. Laheru1, Eric R. Lutz1, Sara Solt1, Aimee Murphy1, Justin Skoble1, Ed Lemmens1, John Grous1, Thomas W. Dubensky1, Dirk G. Brockstedt1, Elizabeth M. Jaffee1
1Dung 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;...
Tóm tắt
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.
