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

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...

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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
Online Access	Get full text
ISSN	1078-8956 1546-170X
DOI	10.1038/nm.4441

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Abstract	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.
AbstractList	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 × 106 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dim 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. Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the treatment of pre–B cell acute lymphoblastic leukemia that is immunotherapy-naive or resistant to CD19-directed CAR T cells.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 × 106 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dim 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. 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.
Author	Delbrook, Cindy Mackall, Crystal L Shah, Nirali N Shern, Jack F Stetler-Stevenson, Maryalice Sabatino, Marianna Orentas, Rimas J Martin, Staci Fountaine, Thomas J Lee, Daniel W Wolters, Pamela Qin, Haiying Nguyen, Sang Stroncek, David F Feng, Yang Dimitrov, Dimiter S Ramakrishna, Sneha Yates, Bonnie Shalabi, Haneen Fry, Terry J Yuan, Constance M Zhang, Ling Majzner, Robbie G Dropulic, Boro
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/29155426$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	Copyright Nature Publishing Group Jan 2018 Springer Nature America, Inc. 2017.
Copyright_xml	– notice: Copyright Nature Publishing Group Jan 2018 – notice: Springer Nature America, Inc. 2017.
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Snippet	Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL),... Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the...
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SubjectTerms	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
Title	CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy
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