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

Abstract

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Figure 1. Comparison of the magnitude of CD8+ T cells specific for mesothelin versus the CEF pool of peptides

An Elispot analysis was performed to determine the number of interferon-gamma secreting T cells specific for mesothelin as described in Table 4. All patient lymphocytes were also assessed for recognition of an HIV negative control peptide and a positive antigen control pool of peptides (CEF pool). Background spots ranged from 0-10 spots/per well as described in Table 4. Graphed is the mesothelin specific T cell response data presented in Table 4 and the corresponding CEF pool specific CD8+ T cell responses. A. Immunotherapy Only Cohort. B. Cyclophosphamide + Immunotherapy Cohort. Striped bars=mesothelin data. Black bars=CEF pool data.