Prof. Zhang Subproject for Institution # SP0052188

The central goal of this project is to evaluate a novel strategy for potentiating antitumor immune responses by engineering natural killer cells to sense and therapeutically respond to general features of the tumor microenvironment. Engineered cell-based therapies are rapidly emerging as clinically relevant technologies for treating cancer, as exemplified by autologous T-cells engineered to express chimeric antigen receptors (CARs) that confer recognition of a specific tumor antigen. While this approach has demonstrated great promise for treating liquid cancers, extension to solid cancers faces many challenges, including an immunosuppressive tumor microenvironment (TME), and lack of targetable surface antigens. Systemic delivery of immune-potentiating factors risks potentially life-threatening toxicities, and engineering cell therapies to constitutively produce immune-potentiating factors may carry similar risks. Intratumoral administration of factors such as cytokines can promote immune control of cancer, but intratumor delivery is not typically feasible, especially for metastatic cancer. To overcome these challenges, we propose to evaluate microenvironment-induced natural killer cells (MINK) as a novel therapeutic strategy for producing immune-potentiating factors specifically at the tumor site, without relying upon pre-identification of tumor-associated antigens.