Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells

• Published in: Leukemia 2016-03, Vol.30 (3), p.701-707
• Main Authors: Pinz, K, Liu, H, Golightly, M, Jares, A, Lan, F, Zieve, G W, Hagag, N, Schuster, M, Firor, A E, Jiang, X, Ma, Y
• Format: Article
• Language: English
• Subjects: 42; 42/100; 631/67/1059/2325; 631/67/1059/602; 631/67/1990/283; 631/67/1990/291/1621/1916; 64/60; 96; 96/106; 96/31; Ablation; Adoptive Transfer; Animals; Antigens; Automobiles; B-cell lymphoma; Blood; Cancer Research; Care and treatment; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell culture; Cell Engineering; Cell Line, Tumor; Cell receptors; Chimeric antigen receptors; Coculture Techniques; Comparative analysis; Complications and side effects; Cord blood; Critical Care Medicine; Culture; Cytotoxicity; Cytotoxicity, Immunologic; Development and progression; Gene Expression; Genetic aspects; Health aspects; Health services; Hematology; Humans; Intensive; Internal Medicine; L-selectin; Leukemia; Leukemia - genetics; Leukemia - immunology; Leukemia - pathology; Leukocytes (mononuclear); Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, T-Cell, Peripheral - genetics; Lymphoma, T-Cell, Peripheral - immunology; Lymphoma, T-Cell, Peripheral - mortality; Lymphoma, T-Cell, Peripheral - therapy; Male; Medicine; Medicine & Public Health; Memory cells; Methods; Mice; Mice, Inbred NOD; Molecular targeted therapy; Mutant Chimeric Proteins - genetics; Mutant Chimeric Proteins - immunology; Neoplasm Transplantation; Non-Hodgkin's lymphomas; Oncology; original-article; Peripheral blood mononuclear cells; Phenotypes; Primary Cell Culture; Receptors; Receptors, Artificial - genetics; Receptors, Artificial - immunology; Risk factors; Stem cells; Survival Analysis; T cell lymphoma
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.311

Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro . CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.