Breaking the immunosuppressive shield of solid tumors of gastrointestinal origin: Multi-armed oncolytic vaccinia virus for in situ vaccination

• Applicant: Dr. Mathilde Feist
• Subject Area: General and Visceral Surgery ; Hematology, Oncology
• Term: from 2016 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320629785

Cancer immunotherapy has become a promising therapeutic modality. Effective immunological treatment of gastrointestinal cancer with the aim to destroy the immunosuppressive shield of the tumor microenvironment (TME) is one of the favorite concepts. Using tumor selective replicating viruses to transform the TME into an in situ vaccine with the potential for systemic effects represents a promising approach in cancer treatment. Bartletts group has developed a tumor-selective oncolytic vaccinia virus (vvDD) which replicates efficiently and selectively in tumors in vivo, which was tested in two clinical phase I trials (intratumoral injection and intravenous injection) at University of Pittsburgh Medical Center (UPMC). The virus proved to be safe and anti-tumor effects were seen. The next step is to express immunogenic transgenes that will lead to an abscopal effect and systemic tumor responses. Multiple chemokine-expressing vvDD constructs are studied and especially expression of CXCL11 (a chemoattractant for activated T-cells) leads to systemic anti-tumor immunity. The project proposed here will investigate the combined expression of CXCL11 and other known immune adjuvants such as PD-1 ectodomain as a decoy receptor for PD-L1 for immune dependent blockade, IL-2 as cytokine stimulating T-cell function and a new developed IL-2/PD-1 fusion protein in gastrointestinal cancer mouse models. Aim of the project is the evaluation of an ideal immunogenic vvDD-construct to maximize the anti-tumor effects and to break the immunosuppressive shield of the tumor microenvironment. After engineering of vaccinia virus vvDD-CXCL11 expressing IL-2, PD-1 or IL-2/PD-1 fusion protein we will examine viral response and tumor response. We will compare different modes of viral delivery, including intravenous, intra-arterial, and intratumoral. We will examine the TME, draining lymph nodes and splenocytes including the immune cell phenotype (suppressor versus effector T-cells, NK cells, and dendritic cells) and the cytokine/chemokine milieu. Moreover, we will assess resistance to tumor re-challenging and adoptive transfer of splenocytes from treated animals as markers of protective, systemic anti-tumor immunity. The expression of CXCL11 and the inhibiting effect of ectodomain of PD-1 by an oncolytic virus has not been described, yet. Their application for enhancing the oncolytic viral therapy is a new promising concept. The IL-2/PD-1 fusion protein has not been previously described and is also a new approach. The unique combination of all these complementary factors has not previously been tested. This project aims to combine multiple immunostimulatory molecules in the context of a potent oncolytic virus for a superior therapeutic efficacy in gastrointestinal cancer models in mice. The novel findings and superior efficacy in preclinical studies may translate into clinical trials in human patients in the near future.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David Bartlett