Dual-Vaccine Combination Improves Survival in Patients with Metastatic Pancreatic Cancer
San Francisco, CA—A dual-vaccine strategy improved survival more than single vaccination of patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Data from a randomized phase 2 trial were reported by Dung T. Le, MD, Assistant Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, at the 2014 Gastrointestinal Cancers Symposium.
First Immunotherapy to Improve Survival
It is the first randomized study to show improved overall survival (OS) for patients with metastatic pancreatic cancer who received immunotherapy.
“This study is just a first step, and we believe we’ll be able to take this approach further,” said Dr Le.
The approach used in the study involves 2 distinct immunotherapy platforms. GVAX is an allogeneic whole-cell vaccine created from 2 pancreatic cancer cell lines. These cells have been genetically modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF).
“The advantage of this platform is that using whole cells allows presentation of a wide variety of tumor-associated antigens to the immune system,” said Dr Le. “The GM-CSF serves to attract dendritic cells to the vaccine site that will then pick up the antigens and present them to the immune system, resulting in an activation of tumor-specific T-cells.” Low-dose intravenous cyclophosphamide is administered the day before GVAX to inhibit regulatory (suppressive) T-cells.
The second immunotherapy platform, CRS-207, is attenuated Listeria monocytogenes, engineered to express mesothelin. Mesothelin is a tumor-associated antigen expressed in a majority of pancreatic cancers. Previous studies have shown that the induction of mesothelin-specific T-cell responses is associated with improved survival.
“Listeria is unique in that it is able to stimulate both innate and adaptive immunity,” Dr Le said. “Because it is an intracellular organism, it has access to both class I and class II antigen-processing pathways and can deliver the encoded antigen directly to the encoded antigen-presenting cell.”
The investigators randomized 90 patients with previously treated, metastatic PDAC in a 2:1 ratio to 2 doses of GVAX and low-dose cyclophosphamide followed by 4 doses of CRS-207, every 3 weeks, or to 6 doses of cyclophosphamide and GVAX every 3 weeks.
At a planned interim analysis, the median OS on an intent-to-treat basis was 6.1 months with the 2-vaccine therapy compared with 3.9 months with GVAX alone. The 1-year survival rate was doubled (24%) with the dual immunotherapy compared with single GVAX (12%). The study met the early stopping rule for efficacy at this interim analysis, said Dr Le.
Among the patients who received at least 3 doses, the median OS was 9.7 months in the dual-vaccine group and 4.6 months in the single-vaccine group (P = .03).
Relatively Mild Side Effects
The vaccine’s side effects were relatively mild and resolved quickly, Dr Le said. Toxicities included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207.
“These are exciting results in a poor-prognosis cancer. This is a phase 2 study, but it is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” said Smitha S. Krishnamurthi, MD, Associate Professor of Medicine, University Hospitals Case Western Reserve University Medical Center, Cleveland, OH. “This is accomplished without the side effects of chemotherapy.”