Adding combination immunotherapy consisting of cancer vaccine, anti-PD-1 and anti-CSF1R antibodies to gemcitabine improves anti-tumor efficacy in murine model of pancreatic ductal adenocarcinoma

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Abstract

Background: Immunotherapy can take advantage of the immunogenic response that chemotherapy elicits in tumors. Gemcitabine is a standard agent used in the treatment of pancreatic cancer, with known effects on the tumor immune microenvironment. The combination immunotherapy of the GVAX cancer vaccine, anti-PD-1 antibody and anti-CSF-1R antibody has been shown to improve survival in a murine model of metastatic pancreatic adenocarcinoma. This combination regimen also increased the infiltration of CD8+ T-cells that expressed both PD1 and CD137, and these T-cells were shown to express high levels of interferon-gamma, a marker of cytotoxic effector CD8+ T-cells. The effect of the addition of gemcitabine to this promising immunotherapy regimen has not been investigated. Methods: Mice with liver-metastatic pancreatic adenocarcinoma were followed for 120 days to determine if adding immunotherapy, which comprised of varying combinations of GVAX, anti-PD-1 antibody and anti- CSF-1R antibody, to gemcitabine improved survival. Tumor-infiltrating CD8+ T-cells and myeloid cells, harvested after the mice were treated for 2 weeks, were analyzed with flow cytometry to characterize the effect the chemo-immunotherapy regimen had on the tumor microenvironment (TME). Results: Adding combination immunotherapy after gemcitabine improved survival compared to gemcitabine treatment alone (gemcitabine/GVAX/anti-PD1, P<0.001; gemcitabine/anti-PD1/anti-CSF-1R, P<0.05; gemcitabine/GVAX/anti-PD1/anti-CSF-1R, P<0.01). However, there was no difference in survival between the three chemo-immunotherapy treatment regimens. Compared to gemcitabine-only treatment, the chemo-immunotherapy regimens also increased the percentage of tumor-infiltrating CD8+ T-cells that expressed interferon-gamma (gemcitabine/GVAX/anti-PD1, P<0.0001 and gemcitabine/GVAX/anti- PD1/anti-CSF-1R, P<0.0001). The chemo-immunotherapy regimens also increased the number of tumor-infiltrating PD1+CD137+CD8+ T-cells and interferon-gamma-expressing PD1+CD137+CD8+ T-cells, but these increases were not statistically significant. Anti-CSF-1R antibody decreased the infiltration of myeloid cells and myeloid-derived suppressor cells caused by GVAX (P<0.05), and trended towards decreasing tumor-associated macrophages (TAMs) (P=0.18). Conclusions: The addition of anti-PD1 antibody with GVAX and/or anti-CSF-1R antibody to gemcitabine improved the survival of mice with liver-metastatic pancreatic ductal adenocarcinoma (PDA). Gemcitabine with GVAX and anti-PD1 with or without anti-CSF-1R also improved the infiltration of effector CD8+ T-cells, and the presence of anti-CSF-1R in the chemo-immunotherapy regimens decreased the infiltration of myeloid cells. The overlapping mechanisms of the components in the chemo-immunotherapy regimens may explain the lack of survival difference between the various regimens, and this remains to be explored.

Original languageEnglish (US)
Article numberA84
JournalAnnals of Pancreatic Cancer
Volume2
DOIs
StatePublished - Dec 2019

Keywords

  • CSF-1R
  • Chemo-immunotherapy
  • GVAX
  • Gemcitabine
  • Pancreatic ductal adenocarcinoma (PDA)

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine
  • Oncology

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