CD19 CAR T-cells expressing IL-12 eradicate lymphoma in fully lymphoreplete mice through induction of host immunity

CAR T-cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ~90% complete remission rates against chemoresistant/refractory CD19+ leukaemia or lymphoma. Effective CAR T-cell therapy is highly dependent on lymphodepleting preconditioning which is achieved through chemotherapy or radiotherapy that carry with them significant toxicities. These can exclude patients of low performance status. In order to overcome the need for preconditioning we constructed fully mouse first and second generation anti-murine CD19 CARs with/without IL-12 secretion. To test these CARs, we established a mouse model to reflect the human situation without preconditioning. Murine second generation CAR T cells expressing IL12 were capable of eradicating established B-cell lymphoma with a long term survival rate of ~25%. We believe this to be the first study in a truly lymphoreplete model. We provide evidence that IL-12 expressing CAR T cells not only directly kill target CD19+ cells, but also recruit host immune cells to an anti-cancer immune response. This finding is critical because lymphodepletion regimens required for the success of current CAR T cell technology eliminate host immune cells who’s anti-cancer activity could otherwise be harnessed by strategies such as IL-12 secreting CAR T cells