Optimization of In Vitro Th17 Polarization for Adoptive Cell Therapy in Chronic Lymphocytic Leukemia

Abstract

Although preclinical investigations have shown notable efficacy in solid tumor models utilizing in vitro-differentiated Th17 cells for adoptive cell therapy (ACT), the potential benefits of this strategy in enhancing ACT efficacy in hematological malignancies, such as chronic lymphocytic leukemia (CLL), remain unexplored. CLL is a B-cell malignancy with a clinical challenge of increased resistance to targeted therapies. T-cell therapies, including chimeric antigen receptor (CAR) T cells, have demonstrated limited success in CLL, which is attributed to CLL-mediated T-cell dysfunction and skewing toward immunosuppressive phenotypes. Herein, we illustrate the feasibility of polarizing CD4+ T cells from the Eμ-TCL1 murine model, the most representative model for human CLL, into Th17 phenotype, employing a protocol of T-cell activation through the inducible co-stimulator (ICOS) alongside a polarizing cytokine mixture. We demonstrate augmented memory properties of in vitro-polarized IL-17-producing T cells, and preliminary in vivo persistence in leukemia-bearing mice. Our findings gain translational relevance through successful viral transduction of Eμ-TCL1 CD4+ T cells with a CD19-targeted CAR construct during in vitro Th17 polarization. Th17 CAR T cells exhibited remarkable persistence upon encountering antigen-expressing target cells. This study represents the first demonstration of the potential of in vitro-differentiated Th17 cells to enhance ACT efficacy in CLL.