Abstract
Combined use of Cy/GVAX and CRS-207 safely increased survival compared with Cy/GVAX alone.
Major finding: Combined use of Cy/GVAX and CRS-207 safely increased survival compared with Cy/GVAX alone.
Concept: Cy/GVAX primes PDAC antigen T-cell responses and CRS-207 boosts mesothelin-specific T-cell induction.
Impact: immunotherapy with this vaccine combination may be beneficial for patients with metastatic PDAC.
Immunotherapy has shown activity in solid tumors and is being explored in pancreatic ductal adenocarcinoma (PDAC), which has a dismal prognosis. Le and colleagues report results of a randomized multicenter phase II trial to compare low-dose cyclophosphamide (Cy) and GVAX (GVAX) followed by CRS-207 with Cy/GVAX alone in 90 patients with pretreated metastatic PDAC. Consisting of two irradiated human PDAC cell lines that secrete granulocyte-macrophage colony-stimulating factor, GVAX induces T-cell responses against PDAC antigens when administered with Cy, which inhibits regulatory T cells. Preclinical and pilot clinical studies have indicated that priming PDAC antigen T-cell responses with Cy/GVAX followed by boosting of T-cell responses against the PDAC antigen mesothelin with CRS-207, a mesothelin-secreting recombinant live-attenuated Listeria monocytogenes vaccine, leads to synergistic antitumor activity compared with either vaccine alone. The primary objective of the trial was to evaluate overall survival, and the secondary objectives were to evaluate safety and clinical responses. The study was stopped at the interim analysis given the improved survival observed in patients who received Cy/GVAX and CRS-207 compared with patients who received Cy/GVAX only. At the updated overall survival analysis, the median overall survival was 6.1 months in the combination arm and 3.9 months in the Cy/GVAX–only arm. In the combination arm, 31% of patients experienced disease stabilization and the 1-year survival probability was 24%, whereas in the Cy/GVAX–only arm 24% of patients had stable disease and patients had a 12% probability of surviving for 1 year. Mesothelin-specific CD8+ T cells were increased above baseline only in the combination arm, and in 44 evaluable patients from both arms, the quantity of mesothelin-specific CD8+ T cells and the breadth of the mesothelin-specific CD8+ T cell repertoire were associated with increased overall survival. These findings provide support for continued evaluation of heterologous prime/boost vaccination with Cy/GVAX and CRS-207 in PDAC and suggest that immunotherapy may be effective in this lethal disease.
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