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<p>B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021–December 2024), 27 (13.6%) developed CirAEs. This included one remarkable case with three distinct CirAEs in association with an extreme CD4<sup>+</sup> CAR T cell expansion (peak lymphocytes: 197 × 10<sup>3</sup> per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, <i>P</i> = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, <i>P</i> = 0.058), peak absolute lymphocyte count ≥ 2.4 × 10<sup>3</sup> per microliter in the first 14 days post-infusion (odds ratio = 4.3, <i>P</i> &lt; 0.001) and apheresis CD4:CD8 ratio &gt; 1 (odds ratio = 2.6, <i>P</i> = 0.048). We identified marked CD4<sup>+</sup> CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4<sup>+</sup> CAR T cell therapy as a key mediator of these toxicities.</p>

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CD4+ T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy

  • 期刊论文

  • 发表日期：

    2026年1月15日

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  • Matthew Ho,
  • Luca Paruzzo,
  • Julia Han Noll,
  • Federico Stella,
  • Pooja Devi,
  • Sonia Ndeupen,
  • Yael A. Day,
  • Gregory M. Chen,
  • Ivan J. Cohen,
  • Angel Ramirez-Fernandez,
  • Adam Waxman,
  • Shivani Kapur,
  • Fang Chen,
  • Rong Xu,
  • Andrew Huff,
  • Danuta Jarocha,
  • Vrutti Patel,
  • Audrey C. Bochi-Layec,
  • Ranjani Ramasubramanian,
  • Shan Liu,
  • Riemke Bouvier,
  • Vitor B. de Souza,
  • Heta Patel,
  • Ziyu Li,
  • Alberto Carturan,
  • Peter Michener,
  • Caitlin R. Hopkins,
  • Owen Koucky,
  • Janna Minehart,
  • Alex Dimitri,
  • Neel R. Nabar,
  • Zainul S. Hasanali,
  • Bryan T. Ciccarelli,
  • Putzer Hung,
  • Erik Williams,
  • Robert Bartoszek,
  • Maya Lavorando,
  • Suyash Mohan,
  • Vanessa E. Gonzalez,
  • Patrizia Porazzi,
  • Vijay G. Bhoj,
  • Sokratis A. Apostolidis,
  • Dan T. Vogl,
  • David L. Porter,
  • John Scholler,
  • Caroline Diorio,
  • Aoife M. Roche,
  • John K. Everett,
  • Frederic D. Bushman,
  • Katherine L. Nathanson,
  • Edward A. Stadtmauer,
  • Sandra P. Susanibar-Adaniya,
  • Alfred L. Garfall,
  • Marco Ruella,
  • Adam D. Cohen,
  • Joseph A. Fraietta

摘要

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021–December 2024), 27 (13.6%) developed CirAEs. This included one remarkable case with three distinct CirAEs in association with an extreme CD4+ CAR T cell expansion (peak lymphocytes: 197 × 103 per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, P = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, P = 0.058), peak absolute lymphocyte count ≥ 2.4 × 103 per microliter in the first 14 days post-infusion (odds ratio = 4.3, P < 0.001) and apheresis CD4:CD8 ratio > 1 (odds ratio = 2.6, P = 0.048). We identified marked CD4+ CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4+ CAR T cell therapy as a key mediator of these toxicities.