Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer.
Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.
The Sidney Kimmel Cancer Center, the Skip Viragh Center for Pancreatic Cancer, Research and Clinical Care, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, MD, USA. dle2@jhmi.edu
Dung T
DT
Le
Eric
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Lutz
Jennifer N
JN
Uram
Elizabeth A
EA
Sugar
Beth
B
Onners
Sara
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Solt
Lei
L
Zheng
Luis A
LA
Diaz
Ross C
RC
Donehower
Elizabeth M
EM
Jaffee
Daniel A
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Laheru
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D060908:CTLA-4 Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D000090204:Mesothelin; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D011859:Radiography; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D058851:GPI-Linked Proteins; D000074324:Ipilimumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000090204:Mesothelin