Ige-Independent Hypersensitvity Reactions Are Associated With Prolonged Survival In Advanced Pancreatic Cancer Patients Receiving A Gm-Csf Cell-Based Vaccine Plus Cyclophosphamide (Cy) And Cetuximab.

Background: Pre-clinical and clinical studies demonstrate that combining Cy with granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting irradiated allogeneic pancreatic tumor cells (pancGVAX) enhances clinical and vaccine induced anti-tumor immune responses. The mechanism is thought to occur by inhibiting suppressor T-cell activity and promoting a type 1 cytotoxic immune response by promoting dendritic cell (DC) activation. Additional pre-clinical evidence support monoclonal antibodies such as Cetuximab that target growth factor receptors (GFRs) in synergistic anti-tumor immune responses. It is estimated that >70% of pancreatic cancers overexpress EGFR. This supports a role for combinatorial immunotherapies in advanced pancreatic cancer. Methods: Sixty patients with advanced pancreatic cancer who progressed on, or refused, first line standard therapy received six cycles of Cy (250 mg/m2) on day 0, pancGVAX (5x108 cells) on day 1, and Cetuximab on days 1, 8 and 15 (initial dose of 400 mg/m2 and subsequent doses of 250 mg/m2) every three weeks. Patients who experienced grade 3 Cetuximab hypersensitivity reactions continued to receive Cy and pancGVAX treatments without further Cetuximab. Serum cytokines and immunoglobulins were analyzed by ELISA and serum cell populations were evaluated using flow cytometry. Results: Twelve out of the 60 patients were hypersensitive to Cetuximab. Median survival was 4.5 months overall. Survival in the hypersensitivity group was 7.1 versus 4.1 months in the non-hypersensitivity group (p=0.026). Baseline characteristics were similar except for the increased number of metastatic disease sites in the hypersensitivity group (2 or more, 100% versus 69%, p=0.027). There was a significant difference in the association between serum IgE levels at enrollment and overall survival for hypersensitive as compared to non-hypersensitive patients (p=0.004). Among hypersensitive patients, higher serum IgE levels at enrollment was associated with increased risk of death (p=0.019, HR =1.05, 95% CI: 1.009 to 1.099). The baseline serum IgE level was not predictive of overall survival for non-hypersensitive patients (p=0.75); however, higher serum IgE levels following the first vaccine was associated with increased risk (p=0.010, HR = 1.026, 95% CI: 1.006 to 1.046). Lower levels of surface IgE bound to plasmacytoid DCs (pDCs), but not monocytoid DCs or basophils, correlated with overall survival both at baseline (p=0.019) and after vaccination (p=0.006). Overall survival also correlated with lower levels of serum IL-6 (p=0.031) and IL-8 (p=0.043). This suggests that a pDC-mediated skewing towards type 2 inflammatory responses is associated with poor prognosis in these patients. Conclusions: Prolonged survival in advanced pancreatic cancer patients correlated with IgE-independent hypersensitivity to Cetuximab. IgE mediated type 2 inflammatory responses are associated with poor prognosis in patients receiving immunotherapy. Blockade of IgE may enhance the efficacy of immunotherapy in pancreatic cancer patients. Citation Format: Julie Ng, Jennifer Uram, Beth Onners, Barbara Biedrzycki, Elizabeth Sugar, Sara Solt, Todd Armstrong, Dung Le, Lei Zheng, John Schroeder, Elizabeth Jaffee, Daniel Laheru. IgE-independent hypersensitvity reactions are associated with prolonged survival in advanced pancreatic cancer patients receiving a GM-CSF cell-based vaccine plus cyclophosphamide (Cy) and cetuximab. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B27.