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Fratricide-resistant CD7-CAR T cells in T-ALL

Nature Medicine volume 30, pages 3687–3696 (2024)Cite this article

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Abstract

T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7− T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.

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Fig. 1: Patient distribution.
Fig. 2: Characteristics of anti-CD7 PEBL-CAR T cells.
Fig. 3: Anti-CD7 PEBL-CAR T cell expansion in patients.
Fig. 4: Antileukemia activity of anti-CD7 PEBL-CAR T cells.
Fig. 5: Immune cell reconstitution after anti-CD7 PEBL-CAR T cell infusion.

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Data availability

The CARTALL trial is currently ongoing. All requests for data related to CARTALL will be considered at the end of the trial. All other requests for data will be considered within 4 weeks, responded to in the context of obligations to patient privacy and confidentiality, and will be subject to review by the study team. Requests can be made to the corresponding authors by email at paeyej@nus.edu.sg. and/or franco.locatelli@opbg.net.

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Acknowledgements

This study was supported by the National Medical Research Council (NMRC) Singapore Translational Research (STaR) Award MOH-000708 (to D.C.), NMRC Research Training Fellowship NMRC/RTF/MOH/000616 (to B.L.Z.O.), NMRC Clinician Scientist Investigator Awards NMRC/CSA/0053/2008 and NMRC/CSA/0053/2013 (to A.E.J.Y.); the Cancer Science Institute of Singapore, National University of Singapore Grant NMRC/CG/NCIS/2010; and the Goh Foundation, Children’s Cancer Foundation, Singapore Totalisator Board, and VIVA Foundation for Children with Cancer. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank X. H. Tan, A. Ummul, D. A. Bte. Roslee, B. S. Lee, D. Ng and T. Y. Whoo for CAR T cell manufacturing; T. G. Soh for cell processing; N. Bte. Hussen, S. Kiong, V. Foo, H. X. Ng, V. Bertaina and C. Quintarelli for flow cytometric studies; Z. Chen, E. K. H. Chiew and G. Liew for regulatory and data management; the Malaysia–Singapore (MASPORE) leukemia study group (A. M. Tan, H. Ariffin, H. P. Lin and L. L. Chan) for providing historical data; M. Kimpo, K. L. Francisco, referring physicians and nursing staff for patient care; and patients and families for participating in the study.

Author information

Authors and Affiliations

  1. Viva-University Children’s Cancer Center, Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore, Singapore

    Bernice L. Z. Oh, Shawn H. R. Lee, Frances Yeap & Allen E. J. Yeoh

  2. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Bernice L. Z. Oh, Noriko Shimasaki, Elaine Coustan-Smith, Shawn H. R. Lee, Frances Yeap, Siew Peng Chen, Allen E. J. Yeoh & Dario Campana

  3. National University Cancer Institute, National University Hospital, National University Health System, Singapore, Singapore

    Esther Chan, Limei Poon, Lip Kun Tan, Allen E. J. Yeoh & Dario Campana

  4. Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore

    Louis Y. A. Chai

  5. Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore, Singapore

    Nina Le Bert, Nicole Tan & Antonio Bertoletti

  6. Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

    Francesca Del Bufalo, Marco Becilli & Franco Locatelli

  7. Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy

    Franco Locatelli

  8. Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Allen E. J. Yeoh & Dario Campana

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  1. Bernice L. Z. Oh
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  2. Noriko Shimasaki
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Contributions

B.L.Z.O. directed cell manufacturing, provided clinical care and performed data analysis. N.S. established cell manufacturing technologies. E.C.-S. analyzed MRD, CAR T cells and immune reconstitution. E.C., L.P., S.H.R.L., F.Y., L.K.T. and L.Y.A.C. provided clinical care. N.L.B., N.T. and A.B. analyzed T cell responses to vaccination. S.P.C. monitored CAR T cells by ddPCR and analyzed MRD. F.D.B. and M.B. provided clinical care and performed data analysis. F.L. provided clinical care and was responsible for the clinical studies in Rome. A.E.J.Y. provided clinical care and was responsible for the clinical studies in Singapore. D.C. initiated the study, directed the translation of the technologies to the clinic and performed data analysis. B.L.Z.O., E.C.-S. and D.C. drafted the manuscript, and all authors reviewed and revised the manuscript.

Corresponding authors

Correspondence to Franco Locatelli or Allen E. J. Yeoh.

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Competing interests

B.L.Z.O., N.S., E.C., L.P., S.H.R.L., F.Y., L.K.T., L.Y.A.C., N.T., S.P.C., F.D.B. and M.B. declare no competing interests. E.C.-S.’s spouse receives royalties for patents related to the development of CAR T cell technologies and is a scientific founder and stockholder of Nkarta Therapeutics and Medisix Therapeutics. N.L.B. is a co-inventor in a pending patent for a method to monitor virus-specific T cells in biological samples. A.B. is a co-inventor in a pending patent for a method to monitor virus-specific T cells in biological samples and is a cofounder of Lion TCR. F.L. has been a consultant for Amgen, Bellicum, Novimmune and Vertex and a speaker for BluebirdBio and Amgen. A.E.J.Y. has been a consultant for Amgen. D.C. receives royalties for patents related to the development of CAR T cell technologies and is a scientific founder and stockholder of Nkarta Therapeutics and Medisix Therapeutics.

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Nature Medicine thanks Kara Davis, Nitin Jain and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Table 1 Demographics and clinical status of the 17 patients with T-ALL treated with anti-CD7 PEBL-CAR-T cells
Full size table
Extended Data Table 2 Baseline demographics and disease characteristics of patients with B-cell ALL (n = 20) treated with anti-CD19 CAR-T cells
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Extended Data Table 3 Demographics and clinical status of the 20 patients with B-cell ALL treated with anti-CD19 CAR-T cells
Full size table
Extended Data Table 4 Characteristics of the anti-CD7 PEBL-CAR-T cell products
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Extended Data Table 5 Lymphodepletion regimens of the patients prior to CAR-T cell infusion
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Extended Data Table 6 Toxicities related to anti-CD7 PEBL-CAR-T cell infusion
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Extended Data Table 7 Summary of toxicities following anti-CD7 PEBL-CAR-T cell therapy prior to HSCT or other therapy
Full size table

Supplementary information

Supplementary Information

Supplementary Table 1 and Figs. 1–11.

Reporting Summary

Supplementary Data

CARTALL study protocol.

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Oh, B.L.Z., Shimasaki, N., Coustan-Smith, E. et al. Fratricide-resistant CD7-CAR T cells in T-ALL. Nat Med 30, 3687–3696 (2024). https://doi.org/10.1038/s41591-024-03228-8

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