Promising Vaccine Combination Identified for Patients With Metastatic Pancreatic Cancer

TOP - May 2014, Vol 7, No 2 - Rare Cancers
Wayne Kuznar

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, at the 2014 Gastrointestinal Cancers Symposium.

It is the first randomized study to show improved overall survival for patients with metastatic pancreatic 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 oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

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 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 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 single vaccination (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, Division of Hematology and Oncology, at Case Western Reserve University School of Medicine, Cleveland, Ohio. “This is accomplished without the side effects of chemotherapy.”

Reference
Le DT, Wang-Gillam A, Picozzi V Jr, et al. A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: updated results. J Clin Oncol. 2014;32(suppl 3):Abstract 177. Presented at: 2014 Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.

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Last modified: May 21, 2015