Description:
<jats:title>Abstract</jats:title>
<jats:p>CAR T cells have had marked success in the treatment of hematologic malignancies such as B-cell acute lymphoblastic leukemia and multiple myeloma. However, some patients fail to have sustained responses, in large part to due limited persistence of their CAR T cells. Previous attempts to prolong CAR T cell survival have attempted to combine CAR T cell therapy and cytokine therapy (IL-2, IL-15) to increase persistence, but this combination of T cell activation and high levels of systemic cytokines can lead to toxicities. To enhance CAR T cell persistence and while mitigating potential cytokine toxicities, we present a bicistronic CAR T engineered to express a membrane-bound drug-degradable IL-7 (mbdIL7) on its surface in addition to a 2nd generation anti-CD19 CAR.</jats:p>
<jats:p>The mbdIL7 is composed of an IL-7 molecule anchored to the cell by a CD80 hinge/transmembrane domain and followed by a cytoplasmic super-degron tag and drives JAK/STAT5 signal transduction. Both mbdIL7 abundance and STAT5 phosphorylation can be efficiently suppressed with lenalidomide, an FDA approved drug, at sub-therapeutic doses. The mbdIL7 can supplant the requirement of exogenous cytokines during manufacturing and leads to a more central memory-biased T cell phenotype. mbdIL7 CAR T cell proliferation remains antigen-dependent. These novel mbdIL7 CAR T cells have similar in vitro effects to traditional CAR T against models of leukemia and lymphoma, but have distinct transcriptional profiles associated with lower levels of exhaustion. In an orthotopic xenograft lymphoma model, mbdIL7 CAR T cells demonstrate markedly enhanced anti-tumor activity compared to traditional anti-CD19 CAR T cells. In addition, mbdIL7 CAR T cells have increased expansion/persistence in the blood, bone marrow, and spleen. The inclusion of a membrane-bound degradable IL-7 into the backbone of a traditional anti-CD19 CAR allows for spatial and temporal control of a pro-persistence cytokine leading to a more effective CAR T treatment. This presents a potential controllable CAR T for patients that are currently not responding conventional FDA-approved products.</jats:p>
<jats:p>Citation Format: Michael C. Kann, Alexander Tepper, Harrison J. Silva, Isabel C. Lane, Amanda A. Bouffard, Rebecca C. Larson, Benjamin L. Ebert, Marcela V. Maus, Max Jan. Lenalidomide switch control of CAR T-cell phenotype and function via degradable membrane-bound IL-7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3606.</jats:p>