Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes –Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer
Open accessAbstract
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.
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Lentiviral vectors have been used to convert the K562 erythroleukemic cell line into artificial antigen-presenting cells that can be used for in vitro T-cell expansion and potentially in vivo vaccination similar to the previously-reported GVAX.
“Lentiviral vectors have also been used to convert the K562 erythroleukemic cell line into artificial antigen-presenting cells that can be used for in vitro T-cell expansion and potentially in vivo vaccination similar to the previously-reported GVAX [96, 97].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [97]
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- Authors
- Le, D. T., Wang-Gillam, A., Picozzi, V., Greten, T. F., Crocenzi, T., Springett, G., Morse, M., Zeh, H., Cohen, D., Fine, R. L., Onners, B., Uram, J. N., Laheru, D. A., Lutz, E. R., Solt, S., Murphy, A. L., Skoble, J., Lemmens, E., Grous, J., Dubensky, T., Brockstedt, D. G., & Jaffee, E. M.
- Affiliations
- Johns Hopkins University (US)
- 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;...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-04-20
- Volume
- 33
- Issue
- 12
- Pages
- 1325-1333
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC4397277
- OpenAlex
- W2151021631
- Cited by
- 611
- References
- 0
- Citations by year
- 2026: 34 · 2025: 48 · 2024: 50 · 2023: 30 · 2022: 42 · 2021: 67 · 2020: 47 · 2019: 46 · 2018: 58 · 2017: 59 · 2016: 75 · 2015: 54 · 2014: 1
- FWCI
- 40.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- National Institutes of Health (KL2TR000450, UL1TR000448)
- National Cancer Institute (K23CA163672, P50CA062924)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- GVAX, Listeria monocytogenes vaccine, CRS-207, mesothelin, metastatic pancreatic adenocarcinoma, cancer immunotherapy, prime-boost vaccination, cyclophosphamide, GM-CSF, CD8+ T cell responses, overall survival, vaccine safety
- MeSH terms
- Mesothelin, Aged, Aged, 80 and over, Combined Modality Therapy, Cyclophosphamide, Female, Humans, Listeria monocytogenes, Male, Middle Aged, Pancreatic Neoplasms, Survival Rate, Antineoplastic Agents, Alkylating, Cancer Vaccines, Carcinoma, Pancreatic Ductal, T-Lymphocytes, Regulatory, GPI-Linked Proteins
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