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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00084383.

Conflict of interest statement

Under a licensing agreement between Cell Genesys and the Johns Hopkins University, the University is entitled to milestone payments and royalties on sales of the vaccine product described in this manuscript. Funding for some of the studies described was provided by Cerus (now Anza) Corporation. Under a licensing agreement involving mesothelin, between Anza and the Johns Hopkins University, Drs. Jaffee and Hruban are entitled to a share of royalties received by the University. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Figures

FIGURE 1

Intervention and data collection schedule.

FIGURE 2

A, Disease-free survival after treatment with allogeneic, irradiated, GM-CSF secreting pancreatic tumor cells as immunotherapy. The survival function is plotted with 95% confidence intervals. The median is denoted with a solid line. B, Overall survival after treatment with allogeneic, irradiated, GM-CSF secreting pancreatic tumor cells as immunotherapy. The survival function is plotted with 95% confidence intervals. The median is denoted with a solid line.

FIGURE 3

Comparison of overall survival for a historical patient cohort resected at JHH who received chemoradiation therapy alone versus patients who received chemoradiation and immunotherapy on study.

FIGURE 4

Postimmunotherapy enhancement of mesothelin-specific CD8+ T cell responses in HLA-A0101+ and HLA-A201+ patients correlates with disease-free survival. IFN gamma ELISPOT assays were performed to measure the frequencies of CD8+ T cells specific for (A) mesothelin epitopes and (B) the CEF pool in peripheral blood leukocytes isolated from HLA-A1+ and HLA-A2+ patients for which pre- and posttreatment lymphocytes were available. Patients were divided into 3 groups: those receiving only one treatment (Single Vaccine, n = 17), those receiving multiple treatments who recurred within 3 years (DFS < 3 year, n = 18), and those receiving multiple treatments who remained disease-free for greater than 3 years (DFS > 3 years, n = 8). Mesothelin responses are reported for the epitope to which each individual patient showed a maximum response. Shown for each group is the median number of IFN gamma-secreting CD8+ T cells per 1 × 106 CD8+ T cells above background measured against irrelevant tumor antigens with the interquartile range. The maximum value for each group is listed above each column. Responses were measured before treatment (pretreatment), 14 days after the first immunotherapy treatment (postvaccine 1) and if given multiple treatments, 28 days after the final immunotherapy treatment (posttreatment). Postimmunotherapy responses were compared to pretreatment responses using 2-tailed Wilcoxon sign-rank tests and the calculated P-values are shown.

FIGURE 5

Longer disease-free survival is associated with an expansion in the repertoire of CD8+ T cells targeted at mesothelin epitopes in HLA-A0101+ and HLA-0201+ patients. IFN gamma ELISPOT assays were performed to measure the frequencies of CD8+ T cells specific for mesothelin epitopes as described in Figure 4. Patients were divided into 3 groups: those receiving only 1 treatment (single vaccine, n = 17), those receiving multiple treatments who recurred within 3 years (DFS < 3 year, n = 18), and those receiving multiple treatments who remained disease-free for greater than 3 years (DFS > 3years, n = 8). Shown are the percentage of mesothelin peptides per patient for which a postimmunotherapy enhancement, defined as a 2-fold or greater increase in the number of IFN gamma-producing peptide-specific T cells was measured after the first (postvaccine 1) and the final immunotherapy treatments (posttreatment, only for patients receiving multiple treatments). Bars represent the overall percentage of peptides for which an enhanced response was measured for each group. Group repertoires were compared using logistic regression and the calculated P values are shown.