Selective support of engineered T cells using a cis-targeted interleukin-2 enhances anti-tumor activity and obviates the need for lymphodepletion

Adoptively transferred T cells require cytokine stimulation, which is achieved using lymphodepleting chemotherapy with or without administration of exogenous interleukin 2 (IL-2). Lymphodepleting chemotherapy (LDC) is associated with cytopenias and attendant complications, while high dose IL-2 causes severe infusion toxicity and can stimulate undesirable cell populations. To address these challenges, we developed cis-targeted IL-2 fusion molecules which are comprised of an IL-2 mutein with attenuated binding to IL-2Rα and IL-2Rβ linked to an antibody that targets a cell-surface molecule expressed specifically on engineered T cells. Using T cells from healthy donors as well as from lymphoma and melanoma patients, we selectively stimulated CAR-T cells or engineered TILs and enhanced their anti-tumor function in multiple tumor models. Finally, we eliminated the need for LDC by combining CAR-T cells with cis-targeted IL-2, leading to B cell aplasia in non-human primates.