Abstract B27: 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
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E-Article
Title:
Abstract B27: 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
Description:
<jats:title>Abstract</jats:title>
<jats:p>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 &gt;70% of pancreatic cancers overexpress EGFR. This supports a role for combinatorial immunotherapies in advanced pancreatic cancer.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>