A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation.

PURPOSE: Surgical resection provides the only possibility of cure for pancreas cancer. A standard adjuvant approach has not been established. We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. PATIENTS AND METHODS: A single institution phase II study of 60 patients with resected pancreatic adenocarcinoma was performed. Each immunotherapy treatment consisted of a total of 5 × 108 GM-CSF-secreting cells distributed equally among 3 lymph node regions. The first immunotherapy treatment was administered 8 to 10 weeks after surgical resection. Subsequently, patients received 5-FU based chemoradiation. Patients who remained disease-free after completion of chemoradiotherapy received treatments 2 to 4, each 1 month apart. A fifth and final booster was administered 6 months after the fourth immunotherapy. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin specific T cell responses. RESULTS: The median disease-free survival is 17.3 months (95% CI, 14.6-22.8) with median survival of 24.8 months (95% CI, 21.2-31.6). The administration of immunotherapy was well tolerated. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival. CONCLUSIONS: An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreas cancer. These data suggest additional boost immunotherapies given at regular intervals beyond 1 year postsurgery should be tested in future studies, and provide the rationale for conducting a multicenter phase II study.

Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation.

PURPOSE: The combination of chemotherapy and immunotherapy has not been examined in patients with advanced pancreatic cancer. We conducted a study of two granulocyte macrophage colony-stimulating factor-secreting pancreatic cancer cell lines (CG8020/CG2505) as immunotherapy administered alone or in sequence with cyclophosphamide in patients with advanced pancreatic cancer. EXPERIMENTAL DESIGN: This was an open-label study with two cohorts: cohort A, 30 patients administered a maximum of six doses of CG8020/CG2505 at 21-day intervals; and cohort B, 20 patients administered 250 mg/m(2) of cyclophosphamide i.v. 1 day before the same immunotherapy given as in cohort A. The primary objective was to evaluate safety and duration of immunity. Secondary objectives included time to disease progression and median overall survival. RESULTS: The administration of CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity. Median survival values in cohort A and cohort B were 2.3 and 4.3 months, respectively. CD8(+) T-cell responses to HLA class I-restricted mesothelin epitopes were identified predominantly in patients treated with cyclophosphamide + CG8020/CG2505 immunotherapy. CONCLUSION: Granulocyte macrophage colony-stimulating factor-secreting pancreatic cancer cell lines CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin-specific T-cell responses were detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, cyclophosphamide-modulated immunotherapy resulted in median survival in a gemcitabine-resistant population similar to chemotherapy alone. These findings support additional investigation of cyclophosphamide with CG8020/CG2505 immunotherapy in patients with advanced pancreatic cancer.