Development and delivery of T cells directed against tumor vascular targets offers multiple theoretical advantages: it can be highly specific, efficient and sustained in time. In addition, it has the potential for significant antigen-induced amplification in vivo and is the only one that can provide long-term memory. Active immunization against tumor-derived endothelial cells has produced encouraging preclinical results but is not a practical approach. Furthermore, generation of T cells with native T cell receptor that exhibits high affinity against ‘self’ tumor endothelial antigens is not straightforward. This proposal will test the central hypothesis that T-body cell therapy is the only form of antioangiogenic gene therapy immediately translatable clinically that can deliver sustained VDA-type effect which is tumor-specific, self-amplifying in vivo and endowed with memory. Coupled with the genetic stability of tumor endothelium and the catastrophic consequences that vascular damage has on the tumor, T-body immune-gene therapy could potentially achieve tumor eradication. Presently, we are the only group in the world with the combined expertise to test this hypothesis. In this proposal we will:
(1) Generate and test in vitro human lymphocytes (T cells) engineered to recognize and attack tumor blood vessels. We will engineer lymphocytes to express several molecules that will direct them to tumor blood vessels and we will compare different molecules to identify those that yield optimal efficacy in vitro.
(2) Test engineered lymphocytes (T cells) engineered to recognize and attack tumor blood vessels in vivo. We will use specialized models of mice developed in our laboratory which can be repopulated with human tumor blood vessels. The optimal vector will be selected for clinical development from these in vivo studies. (
3) Conduct a phase I trial to test the safety and anti-tumor efficacy of lymphocytes (T cells) engineered to recognize and attack tumor blood vessels in patients with advanced, recurrent ovarian and peritoneal cancer. Taken together, a translational team of basic scientists and clinicians will provide the first comprehensive evaluation of the use of this redirected T cell concept to implement antiangiogenic immune-gene therapy in cancer patients.