Neoadjuvant in situ gene-mediated cytotoxic immunotherapy improves postoperative outcomes in novel syngeneic esophageal carcinoma models

Abstract

Esophageal carcinoma is the most rapidly increasing tumor in the United States and has a dismal 15% 5-year survival. Immunotherapy has been proposed to improve patient outcomes; however, no immunocompetent esophageal carcinoma model exists to date to test this approach. We developed two mouse models of esophageal cancer by inoculating immunocompetent mice with syngeneic esophageal cell lines transformed by cyclin-D1 or mutant HRASG12V and loss of p53. Similar to humans, surgery and adjuvant chemotherapy (cisplatin and 5-fluorouracil) demonstrated limited efficacy. Gene-mediated cyototoxic immunotherapy (adenoviral vector carrying the herpes simplex virus thymidine kinase gene in combination with the prodrug ganciclovir; AdV-tk/GCV) demonstrated high levels of in vitro transduction and efficacy. Using in vivo syngeneic esophageal carcinoma models, combining surgery, chemotherapy and AdV-tk/GCV improved survival (P=0.007) and decreased disease recurrence (P<0.001). Mechanistic studies suggested that AdV-tk/GCV mediated a direct cytotoxic effect and an increased intra-tumoral trafficking of CD8 T cells (8.15% vs 14.89%, P=0.02). These data provide the first preclinical evidence that augmenting standard of care with immunotherapy may improve outcomes in the management of esophageal carcinoma.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…49 In both mouse models and patients with esophageal squamous cell carcinoma, neoadjuvant chemotherapy with 5-FU and cisplatin increased the intratumoral trafficking of CD4 and CD8 T-cells. 50,51 In experimental carcinogen-induced adenocarcinomas and fibrosarcomas, doxorubicin treatment enhanced tumor-specific proliferation of CD8 T-cells in tumor-draining lymph nodes (LNs) and promoted tumor infiltration of activated, IFN-g-producing CD8 T-cells. 52 In this setting, therapeutic efficacy of doxorubicin required both IL-1b and IL-17, and the presence of gd T-cells.…”

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

“…This strategy has theoretical benefits such as low toxicity, tumor specificity, and long-lasting immunity. Most importantly, cancer vaccines are maximally effective for limited disease burden; thus postoperative administration is appealing because of the presence of minimal residual disease (4,6,7,8).…”

Surgical cytoreduction restores the antitumor efficacy of a Listeria monocytogenes vaccine in malignant pleural mesothelioma

“…Surgery may enhance immunotherapy not only through simple mechanical cytoreduction, but also by reducing systemic tumor-related immunosuppression. 25,41,46 Here, we demonstrate that surgery reduces systemic myeloid derived suppressor populations, which are known to inhibit CD8 T-cell responses. This approach is not without limitations, as surgery has been shown to generate a transiently immunosuppressive tumor microenvironment that allows increased tumor growth.…”