To overcome the toxicity of prior lymphodepletion in CAR T cell therapy, Kueberuwa et al. created a lymphoreplete mouse model of CD19+ B cell lymphoma and demonstrated that murine CD19 CAR T cells expressing IL-12 were able to eradicate the tumor and confer long-term survival in approximately 25% of mice. The antitumor response was due to both direct killing by the CAR T cells and recruitment of host immune cells (a.k.a. epitope spreading), a beneficial effect potentially subverted by the current practice of lymphodepletion.

Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown approximately 90% complete remission rates against chemoresistant and/or refractory CD19(+) leukemia or lymphoma. Effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, which is achieved through chemotherapy or radiotherapy that carries with it 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 or without interleukin-12 (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 IL-12 were capable of eradicating established B cell lymphoma with a long-term survival rate of approximately 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 whose anti-cancer activity could otherwise be harnessed by strategies such as IL-12-secreting CAR T cells.

Author Info: (1) Institute of Cancer Sciences, Manchester Cancer Research Centre Building, Wilmslow Road, Withington, Manchester M20 4QL, UK. (2) Institute of Cancer Sciences, Manchester Cancer

Author Info: (1) Institute of Cancer Sciences, Manchester Cancer Research Centre Building, Wilmslow Road, Withington, Manchester M20 4QL, UK. (2) Institute of Cancer Sciences, Manchester Cancer Research Centre Building, Wilmslow Road, Withington, Manchester M20 4QL, UK. (3) Institute of Cancer Sciences, Manchester Cancer Research Centre Building, Wilmslow Road, Withington, Manchester M20 4QL, UK. (4) Institute of Cancer Sciences, Manchester Cancer Research Centre Building, Wilmslow Road, Withington, Manchester M20 4QL, UK. (5) Institute of Cancer Sciences, Manchester Cancer Research Centre Building, Wilmslow Road, Withington, Manchester M20 4QL, UK.