Chimeric antigen receptor-modified T cells derived from defined [CD8.sup.+] and [CD4.sup.+] subsets confer superior antitumor reactivity in vivo

• Published in: Leukemia p. 492
• Main Authors: Sommermeyer, D, Hudecek, M, Kosasih, P.L, Gogishvili, T, Maloney, D.G, Turtle, C.J, Riddell, S.R
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01-02-2016
• Subjects: Antigen receptors, T cell; Cancer; Health aspects; Immune response; Oncology, Experimental; Receptors; Regulation; T cells
• ISSN: 0887-6924
• DOI: 10.1038/Leu.2015.247

Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of [CD4.sup.+] and [CD8.sup.+] naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets ([CD4.sup.+]/[CD8.sup.+] naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent [CD4.sup.+] and [CD8.sup.+] CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies. Leukemia (2016) 30, 492-500; doi:10.1038/Leu.2015.247