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 × 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.

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Acknowledgements

We gratefully acknowledge the study participants and their families, referring medical care teams, the faculty and staff of the NIH and the data managers involved with this work. This work was supported in part by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health, by a Stand Up to Cancer–St. Baldrick's Pediatric Dream Team translational research grant (SU2C-AACR-DT113) and by a St. Baldrick's Foundation Scholar Award (D.W.L.). Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. C.L.M. is a member of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University Cancer Immunotherapy Program. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Author notes

    • Rimas J Orentas
    • , Boro Dropulic
    •  & Daniel W Lee

    Present addresses: Lentigen Technology, Inc., Miltenyi Biotec, Gaithersburg, Maryland, USA (B.D. and R.J.O.) and Division of Pediatric Hematology & Oncology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA (D.W.L.).

Affiliations

  1. Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Terry J Fry
    • , Nirali N Shah
    • , Rimas J Orentas
    • , Sneha Ramakrishna
    • , Pamela Wolters
    • , Staci Martin
    • , Cindy Delbrook
    • , Bonnie Yates
    • , Haneen Shalabi
    • , Thomas J Fountaine
    • , Jack F Shern
    • , Ling Zhang
    • , Sang Nguyen
    • , Haiying Qin
    •  & Daniel W Lee
  2. Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, Maryland, USA.

    • Maryalice Stetler-Stevenson
    •  & Constance M Yuan
  3. Department of Pediatrics, Stanford University, Stanford, California, USA.

    • Robbie G Majzner
  4. Department of Transfusion Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.

    • David F Stroncek
    •  & Marianna Sabatino
  5. Cancer and Inflammation Program, National Cancer Institute, NIH, Bethesda, Maryland, USA.

    • Yang Feng
    •  & Dimiter S Dimitrov
  6. Lentigen Corporation, Gaithersburg, Maryland, USA.

    • Boro Dropulic
  7. Department of Pediatrics and Standford Cancer Center, Stanford University, Stanford, California, USA.

    • Crystal L Mackall

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Contributions

T.J. Fry, N.N.S., R.J.O., D.S.D., B.D., D.W.L. and C.L.M. designed the study. T.J. Fry, N.N.S., M.S.-S., C.M.Y., C.D., B.Y., H.S., D.F.S., M.S., Y.F., P.W., S.M., D.W.L., T.J. Fountaine, J.F.S., L.Z., S.N., H.Q., P.W., S.R., R.G.M. and C.L.M. generated and analyzed the data. T.J. Fry, N.N.S. and C.L.M. vouch for the data and the analysis, wrote the paper and decided to publish the paper. No nonauthor wrote the first draft or any part of the paper.

Competing interests

C.L.M. and R.J.O. are inventors on a patent for the CD22-directed CAR (US Patent and Trademark Office, 20140274909).

Corresponding author

Correspondence to Terry J Fry.

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DOI

https://doi.org/10.1038/nm.4441