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

• Published in: Leukemia Vol. 30; no. 2; pp. 492 - 500
• 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: London Nature Publishing Group UK 01-02-2016; Nature Publishing Group
• Subjects: 13; 42; 42/44; 59/5; 631/250/1619/554; 631/250/580; 631/61/51/1844; 631/67/1059/2325; 692/308/2778; 692/699/67/1990/291; Animals; Anticancer properties; Antigens; Antitumor activity; Cancer Research; CD19 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell therapy; Chemical compounds; Chimeric antigen receptors; Clinical trials; Composition; Critical Care Medicine; Effector cells; Female; Hematology; Humans; Immunologic Memory; Immunological memory; Immunotherapy, Adoptive; Intensive; Internal Medicine; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine; Medicine & Public Health; Memory cells; Mice; Neoplasms - therapy; Oncology; original-article; Patients; Pharmacology; Receptors; Receptors, Antigen, T-Cell - immunology; Recombinant Fusion Proteins - immunology; Solid tumors; T cell receptors; Tumors
• ISSN: 0887-6924; 1476-5551
• 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
+
and CD8
+
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
+
/CD8
+
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
+
and CD8
+
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.