CAR T cell therapy: inroads to response and resistance

• Published in: Nature reviews. Immunology Vol. 19; no. 2; pp. 73 - 74
• Main Authors: Brown, Christine E., Mackall, Crystal L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 631/250/1619/554/1834/1269; 631/67/1059/2326; 692/4028/67/1059/2325; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Antigens; Biomedical and Life Sciences; Biomedicine; Care and treatment; CD19 antigen; CD22 antigen; CD8 antigen; Cell differentiation; Chimeric antigen receptors; Chronic lymphocytic leukemia; Development and progression; Dioxygenase; Exhaustion; Fitness; Health aspects; Humans; Immunology; Immunotherapy; Immunotherapy, Adoptive - methods; Leukemia; Leukemia - immunology; Leukemia - therapy; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma - immunology; Lymphoma - therapy; Memory cells; Receptors, Antigen, T-Cell - immunology; Remission; Solid tumors; T-Lymphocytes - immunology; Year in Review; United States
• ISSN: 1474-1733; 1474-1741
• DOI: 10.1038/s41577-018-0119-y

Here, we highlight key papers published in 2018 that advance our understanding of resistance to chimeric antigen receptor (CAR) T cell immunotherapy for leukaemia and lymphoma and in so doing reveal barriers that must be addressed to increase efficacy of this novel class of therapeutics for B cell malignancies and expand their reach to solid tumours. Several clinical studies in 2018 documented the potency of therapies based on T cells with chimeric antigen receptors (CAR T cells), but also revealed mechanisms of resistance. These insights may facilitate the design of improved CAR T cell therapies for B cell malignancies and beyond. Key advances CD19-targeted chimeric antigen receptor (CAR) T cells induce high complete response rates in paediatric B cell acute lymphoblastic leukaemia (B-ALL) cases, but many of these patients will relapse, most often with CD19-negative leukaemia. CD22-directed CAR T cells induce high response rates in CD19-naive or CD19-resistant B-ALL, but often relapse with CD22 lo leukaemia. Intrinsic gene programmes of memory versus exhaustion correlate with T cell fitness and determine response to CD19-targeted CAR T cells in chronic lymphocytic leukaemia (CLL). Loss of Tet methylcytosine dioxygenase 2 (TET2), an epigenetic modulator, prevented terminal T cell differentiation and enabled the progeny of a single CD8 + CAR T cell clone to mediate complete remission in a patient with CLL.