CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy

• Published in: Nature medicine Vol. 24; no. 1; pp. 20 - 28
• Main Authors: Fry, Terry J, Shah, Nirali N, Orentas, Rimas J, Stetler-Stevenson, Maryalice, Yuan, Constance M, Ramakrishna, Sneha, Wolters, Pamela, Martin, Staci, Delbrook, Cindy, Yates, Bonnie, Shalabi, Haneen, Fountaine, Thomas J, Shern, Jack F, Majzner, Robbie G, Stroncek, David F, Sabatino, Marianna, Feng, Yang, Dimitrov, Dimiter S, Zhang, Ling, Nguyen, Sang, Qin, Haiying, Dropulic, Boro, Lee, Daniel W, Mackall, Crystal L
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2018
• Subjects: Acute lymphoblastic leukemia; Adolescent; Adult; Adults; Anticancer properties; Antigens; Antigens, CD19 - immunology; Biological activity; Biological effects; Body weight; Bone marrow; CD19 antigen; CD22 antigen; Cell therapy; Chemotherapy; Child; Children; Chimeric antigen receptors; Cytokines - metabolism; Density; Flow cytometry; Humans; Hypoxia; Immunotherapy; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Lymphocytes T; Neurotoxicity; Patients; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors; Receptors, Chimeric Antigen - immunology; Remission; Remission (Medicine); Remission Induction; Sepsis; Sialic Acid Binding Ig-like Lectin 2 - immunology; Toxicity; Young Adult
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4441

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 10 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19 or CD19 B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22 cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.