Saung et al. investigated CSF-1R within lymphoid aggregates that were induced in surgically resected human pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant GVAX, a GM-CSF-secreting cell vaccine. High CSF-1R levels were associated with immunosuppressive myeloid infiltrate and immature DCs. In a therapeutic mouse model of metastatic PDAC, one cycle of anti-CSF-1R Ab pre- and post- GVAX + anti-PD-1 treatment enhanced CD137 (4-1BB) and OX40 expression on infiltrating T cells and improved day 23, but not overall, survival. A higher fraction of CD8+PD-1+CD137+ cells expressed IFNγ compared to CD137- cells.
BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/alphaPD-1). Resistance to GVAX was associated with an immune-suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/alphaPD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated. METHODS: Lymphoid aggregates appreciated in 24 surgically resected PDAC from patients who received one dose of neoadjuvant GVAX were analyzed with multiplex immunohistochemistry. Flow cytometry analysis of tumor infiltrating T-cells in a murine model of PDAC was performed to investigate the therapeutic effects and mechanism of anti-CSF-1R/anti-PD-1/GVAX combination immunotherapy. RESULTS: High CSF-1R expression in resected PDAC from patients who received neoadjuvant GVAX was associated with a higher myeloid to lymphoid cell ratio (p < 0.05), which has been associated with poorer survival. This higher CSF-1R expression was associated with a higher intra-tumoral infiltration of immature dendritic cells (p < 0.05), but not mature dendritic cells (p = 0.132). In the pre-clinical murine model, administering anti-CSF-1R antibody prior to and after GVAX/alphaPD-1 ("pre/post-alphaCSF-1R + alphaPD-1 + GVAX") enhanced the survival rate compared to GVAX/alphaPD-1 dual therapy (p = 0.005), but administering anti-CSF-1R only before GVAX/alphaPD-1 did not (p = 0.41). The "pre/post-alphaCSF-1R + alphaPD-1 + GVAX" group also had higher intra-tumoral infiltration of PD-1 + CD8+ and PD-1 + CD4+ T-cells compared to alphaPD-1/GVAX (p < 0.001). Furthermore, this regimen increased the intra-tumoral infiltration of PD-1 + CD137 + CD8+, PD-1 + CD137 + CD4+ and PD-1 + OX40 + CD4+ T-cells (p < 0.001). These PD-1 + CD137 + CD8+ T-cells expressed high levels of interferon-gamma (median 80-90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1 + CD137-CD8+ T-cells (p < 0.001). CONCLUSIONS: The conversion of exhausted PD-1+ T-cells to CD137+ activated effector T-cells may contribute to the anti-tumor effects of the anti-CSF-1R/anti-PD-1/GVAX combination therapy. Anti-CSF-1R antibody with anti-PD-1 antibody and GVAX have the potential be an effective therapeutic strategy for treatment of PDAC.
Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (7) Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, USA. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (8) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (9) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu. The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu. Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu. The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.
