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CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results

Nature Medicine volume 29, pages 1710–1717 (2023)Cite this article

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Abstract

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.

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Fig. 1: Patient distribution.
Fig. 2: Rates of CRS and ICANS in the 31 patients treated with prophylactic anakinra.
Fig. 3: Response of patients with relapsed and refractory lymphoma.
Fig. 4: Serum and CSF cytokine changes over time in study.

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Data availability

This trial is currently ongoing. Subject to patient privacy and confidentiality obligations, access to patient-level data and supporting clinical documents will be available upon request and subject to review by the study sponsor and/or the corresponding author on completion of the trial. Such requests can be made to the corresponding author by email at parkj6@mskcc.org. Any data and materials that can be shared will be released via a material transfer agreement and/or data access agreement.

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Acknowledgements

This research was supported by the Geoffrey Beene Foundation Grant (to J.H.P.) and in part by NIH/NCI Cancer Center Support grant P30 CA008748. The drug supply (anakinra) was provided by Sobi. Sobi did not have any oversight of the trial and was not involved in writing the trial report. The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health.

Author information

Author notes

  1. Craig S. Sauter

    Present address: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

  2. Ana Alarcon Tomas

    Present address: Division of Hematology and Hemotherapy, Hospital General Universitario Gregorio Maranon, Madrid, Spain

  3. Renier J. Brentjens

    Present address: Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

  4. These authors contributed equally: Jae H. Park, Karthik Nath.

Authors and Affiliations

  1. Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Jae H. Park, Karthik Nath, Craig S. Sauter, M. Lia Palomba, Gunjan Shah, Parastoo Dahi, Richard J. Lin, Michael Scordo, Miguel-Angel Perales, Roni Shouval, Elizabeth Cathcart, Elena Mead, Bianca Santomasso & Renier J. Brentjens

  2. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Jae H. Park

  3. Department of Medicine, Weill Cornell Medicine, New York City, NY, USA

    Jae H. Park, M. Lia Palomba, Gunjan Shah, Parastoo Dahi, Richard J. Lin, Michael Scordo, Miguel-Angel Perales & Roni Shouval

  4. Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Sean M. Devlin

  5. Center for Cell Engineering, Sloan Kettering Institute, New York City, NY, USA

    Craig S. Sauter, Renier J. Brentjens, Isabelle Riviere & Michel Sadelain

  6. Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    M. Lia Palomba

  7. Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Gunjan Shah, Parastoo Dahi, Richard J. Lin, Michael Scordo, Miguel-Angel Perales, Roni Shouval & Ana Alarcon Tomas

  8. Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Elena Mead

  9. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Bianca Santomasso

  10. Radiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Andrei Holodny

  11. Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Isabelle Riviere

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Contributions

J.H.P. designed the initial study protocol. R.J.B., I.R. and M.S. provided support for the overall trial design. J.H.P., K.N., C.S., M.L.P., G.S., P.D., R.J.L., M.S., M.-A.P., R.S., A.A.T., E.M. and B.S. provided clinical care for the patients enrolled in the study. E.C. provided support for the clinical operation of the study. E.C., R.S. and A.A.T. provided support for data entry. A.H. performed tumor volume assessment. J.H.P., K.N. and S.D. performed the clinical data analysis and S.D. did the statistical analysis. J.H.P. and K.N. drafted the manuscript, and all authors have reviewed and participated in the revisions of the manuscript.

Corresponding author

Correspondence to Jae H. Park.

Ethics declarations

Competing interests

J.H.P. received consulting fees from Affyimmune Therapeutics, Amgen, Autolus, Be Biopharma, Beigene, Bright Pharmaceutical Services, Inc., Curocel, Kite, Medpace, Minerva Biotechnologies, Pfizer, Servier, Sobi and Takeda; received honoraria from OncLive, Physician Education Resource, and MJH Life Sciences; serves on scientific advisory board of Allogene Therapeutics and Artiva Biotherapeutics; and received institutional research funding from Autolus, Genentech, Fate Therapeutics, InCyte, Servier and Takeda. C.S.S. has served as a paid consultant to Juno Therapeutics, Sanofi-Genzyme, Spectrum Pharmaceuticals, Novartis, Genmab, Precision Biosciences, Kite/a Gilead Company, Celgene/BMS, Gamida Cell, Karyopharm Therapeutics, MorphoSys, CSL Behring, Syncopation Life Sciences, CRISPR Therapeutics and GSK; serves on DSMBs for Ono Pharmaceuticals and CRISPR Therapeutics; and has received research funds for clinical trials from Juno Therapeutics, Celgene/BMS, Bristol Myers Squibb, Precision Biosciences, Actinium Pharmaceuticals, Sanofi-Genzyme and NKARTA. M.L.P. received consulting fees from BMS, Cellectar, Kite, Mustang Bio and Synthekine. G.S. received consulting fees from Amgen, BMS, Beyond Spring, and Janssen and serves on DSMB for Arcellx. P.D. received consulting fees from Kite. R.J.L. received consulting fees from Kite and Priothera. M.S. served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, Inc., Kite and Omeros Corporation; received research funding from Angiocrine Bioscience, Inc., Omeros Corporation and Amgen, Inc.; and has received honoraria from i3Health and Medscape for CME-related activity. M.-A.P. reports personal fees from Adicet, Allovir, Caribou Biosciences, Celgene, BMS, Equilium, Exevir, Karyopharm, Merck, MorphoSys, Omeros, Syncopation, VectivBio AG, Vor Biopharma, Cidara Therapeutics, Medigene, Sellas Life Sciences and NexImmune; personal fees and other support from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics and Novartis; and other support from OrcaBio outside the submitted work. B.S. is an inventor on United States Provisional Patent Application No. US20210181179A1 ‘Diagnosis and treatment of immunotherapy-induced neurotoxicity’ filed by Memorial Sloan Kettering Cancer Center and served in a consulting or advisory role for Celgene, Janssen, Legend Biotech, Incyte, Kite/Gilead and In8bio. A.H. is an owner/president of fMRI Consultants, LLC. R.J.B. has licensed intellectual property to and collected royalties from BMS, Caribou and Sanofi; received research funding from BMS; is a consultant to BMS, Atara Biotherapeutics Inc., CoImmune and Triumvira; was a consultant for Gracell Biotechnologies Inc but ended employment in the past 30 months; and is a member of the scientific advisory board for CoImmune and Triumvira. I.R. reports grants from Takeda Pharmaceuticals and Atara, personal fees from Mnemo Therapeutics, Akron, the Centre for Commercialization of Cancer and Oribiotech, and other support from Bristol Myers Squibb outside the submitted work. M.S. reports grants from Atara Biotherapeutics outside the submitted work, as well as patent 8389282 issued and licensed to Juno Therapeutics, patent 11242375 issued and licensed to Atara Biotherapeutics, patent 10370452 issued, licensed and with royalties paid from Fate Therapeutics, patent 11377637 issued and licensed to Takeda Pharmaceuticals, patent 11377637 issued and licensed to Mnemo Therapeutics, and patent 11377637 issued and licensed to Minerva Biotechnologies. The remaining authors declare no competing interests.

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Nature Medicine thanks Frederick Locke, Jongphil Kim and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Response of patients with relapsed and refractory lymphoma.

(2a) Best response by day 100 post CAR T-cell infusion displayed by the cell products received. (2b) Overall survival (2c) progression free survival of the study patients separated by LBCL vs. mantle cell lymphoma CAR denotes chimeric antigen receptor; ORR denotes overall response rate; PD denotes progressive disease; LBCL denotes large B-cell lymphoma; *One patient died of COVID-19 pneumonia at day 47 and did not have day 30 response assessment – this patient is included in the PD category.

Extended Data Fig. 2 Serum cytokine changes over time on study.

Changes in the level of serum cytokines after anakinra administration separated by grade 0–2 ICANS vs. grade 3–4 ICANS (n = 31).

Extended Data Table 1 Antimicrobial prophylaxis guidelines
Full size table
Extended Data Table 2 Baseline patient and disease characteristics
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Extended Data Table 3 Baseline characteristics, toxicity management and clinical outcomes of all patients
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Extended Data Table 4 Anakinra administration schedules and dose escalation indication
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Extended Data Table 5 Neurological symptoms observed in the study and CTCAE grading
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Extended Data Table 6 Tocilizumab and corticosteroid use and indications
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Extended Data Table 7 Infectious complications after CAR T-cell infusion in all patients
Full size table

Supplementary information

Supplementary Information

Supplementary Note—study protocol.

Reporting Summary

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Park, J.H., Nath, K., Devlin, S.M. et al. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results. Nat Med 29, 1710–1717 (2023). https://doi.org/10.1038/s41591-023-02404-6

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