Promising Vaccine Combination Identified for Patients With Metastatic Pancreatic Cancer
A dual vaccine strategy improved survival more than a single vaccine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Data from a randomized phase 2 trial were reported by Dung T. Le, MD.
It is the first randomized study to show improved overall survival for patients with metastatic pancreas cancer treated with immunotherapy.
“This study is just a first step, and we believe we’ll be able to take this approach further,” said Le, assistant professor of medicine, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
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 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 IV 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 elicit an immune response against mesothelin. Mesothelin is a tumor-associated antigen expressed in a majority of pancreatic cancers. Prior studies have shown that induction of mesothelin-specific T-cell responses is associated with improved survival.
The modified strain of Listeria decreases pathogenicity but retains immunogenicity. “Listeria is unique in that it is able to stimulate both innate and adaptive immunity,” she 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 study 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 overall survival on an intent-to-treat basis was 6.1 months with the 2-vaccine therapy compared with 3.9 months with GVAX alone (P=.0343). One-year survival was doubled by giving dual immunotherapy compared with single GVAX (24% vs 12%). The study met the early stopping rule for efficacy at this interim analysis, said Le.
Among the patients who received at least 3 doses (per protocol analysis), the median survival was 9.7 months in the group randomized to dual vaccine and 4.6 months in those randomized to a single vaccine (P=.03).
The side effects of the vaccine were relatively mild and resolved quickly, she 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 Krishnamurthi, MD, associate professor of medicine, University Hospitals Case Medical Center, Cleveland, OH. “This is accomplished without the side effects of chemotherapy.”
A new study presented at ASCO 2018 showed that the use of next-generation sequencing of metastatic non–small-cell lung cancer tumors to test for all known cancer-related genetic mutations was more cost-effective and provided faster results than testing for a single genetic mutation.
Reprogramming patients’ immune cells to treat their cancer has become the front line of cancer therapy, with chimeric antigen receptor (CAR) T-cell therapy now approved by the FDA for several blood cancers. But translating this success to solid tumors remains a challenge. At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Gianpietro Dotti, MD, Cancer Cellular Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, discussed efforts to extend the application of CAR T-cell therapy to solid tumors.