Game Changer Grant Awarded to Hideho Okada and Wendell Lim

Immunotherapy using genetically engineered lymphocytes, such as T cells, has made tremendous progresses in the last decade, and a chimeric antigen receptor (CAR)-transduced T cell (CART) therapy is now available for patients with blood cancer. However, effective CART therapy for solid cancers, including brain tumors, must still overcome multiple challenges. One major challenge is to ensure that engineered T cells only attack tumor cells and not normal cells. This is particularly important for pediatric patients with DIPG as their normal organs are still developing. Engineered T cells are trained to recognize antigens expressed by the tumor cells, identifying the tumor cells for elimination. However, there are no antigens that are exclusively present on DIPG tumor cells and not also found on normal cells in organs throughout the body. While these barriers have impeded the development of successful immunotherapy for DIPG, our ability to engineer lymphocytes has greatly advanced in the last several years and we are now investigating a novel strategy to ensure tumor-selective effects of CART therapy for DIPG patients.

We have developed innovative CART circuits that recognize tumor cells based on sequential antigen combinations. These circuits use a “prime-and-kill” strategy, in which the first antigen, which is uniquely expressed on cells in the brain or brain tumor, primes the T lymphocytes to express a CAR to kill nearby tumor cells expressing antigens only found on tumor cells but not normal cells in the brain. While the CAR-target antigens are often expressed on cells in the normal organs outside of the brain, the priming antigens ensure that the immune response is localized within the brain. Therefore, without this switch system, CART cells that target these antigens would damage normal organs as already seen in some clinical trials.

In this grant proposal, we will evaluate our “prime-and-kill” strategy using preclinical models of DIPG. Our preliminary data suggest that this system may work in DIPG models, and we have selected antigens that are suitable for DIPG. Our goal is to identify and establish antigen combinations that could be used to safely treat DIPG. These studies will provide an important basis to develop first-in-man clinical trials of this approach.