Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths in the US; with less than one-year median survival, it accounts for approximately 30,000 diagnoses and deaths per year. Multimodality therapy, including surgery, radiation and chemotherapy, have not made a significant impact on the outcome and serve mostly as palliation. Thus, new treatment approaches are desperately needed for pancreatic cancer. Advantagene has been developing technologies that may improve the outcome of these standard therapies. Advantagene's lead technology platform, Gene Mediated Cytotoxic Immunotherapy (GMCI(tm)), is an approach which generates a systemic tumor vaccine effect through local delivery of an adenoviral vector (AdV-tk) expressing HSV-tk (TK) when combined with standard therapies. This approach has shown activity in many preclinical tumor models and demonstrated safety with potential efficacy in Phase I and Phase II clinical trials. GMCI(tm) has not been clinically evaluated in pancreatic cancer. The hypothesis for the mechanism, supported by preliminary studies, involves TK-specific cytotoxic and immune-stimulatory properties: (1) local TK-mediated tumor cell killing is appropriate to induce a """"""""danger"""""""" microenvironment, (2) radiation induces an acute inflammatory response that potentiates uptake and presentation of TK-released tumor associated antigens by antigen presenting cells, and (3) effector T cell stimulation is potentiated by a superantigen-like effect of the TK molecule. The clinical hypothesis is that the resultant anti-tumor immunity will decrease the incidence or significantly delay local progression and metastases in pancreatic cancer patients. Pancreatic cancer provides an opportunity to evaluate the cytotoxic and immunostimulatory activity of GMCI(tm) and correlate this with clinical outcome. This Phase 1 grant is to support the first Phase I clinical trial to apply this technology in pancreatic cancer (Aim 1 and 2) and evaluate biologic activity in tumor specimens after treatment (Aim 3). The primary goal of this Phase 1 application is to evaluate the safety of GMCI(tm) with AdV-tk in pancreatic cancer and to evaluate vector function in pancreatic cancer in vivo. The hypothesis is that a safe and active vector dose will be identified that can be evaluated in a subsequent Phase II trial. The Phase II trial is the subject of the Phase 2 portion of this Fast-track application. ? ?
| Aguilar, Laura K; Shirley, Lawrence A; Chung, Vincent M et al. (2015) Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma. Cancer Immunol Immunother 64:727-36 |
| Shirley, Lawrence A; Aguilar, Laura K; Aguilar-Cordova, Estuardo et al. (2013) Therapeutic endoscopic ultrasonography: intratumoral injection for pancreatic adenocarcinoma. Gastroenterol Res Pract 2013:207129 |
| Aguilar, Laura K; Guzik, Brian W; Aguilar-Cordova, Estuardo (2011) Cytotoxic immunotherapy strategies for cancer: mechanisms and clinical development. J Cell Biochem 112:1969-77 |
