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<p>We performed the first in-depth, comparative and prospective biomonitoring of Multiple Myeloma (MM) patients (<i>N </i>= 39) receiving ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel (ide-cel) chimeric antigen receptor T cells (CAR T) in the real-world setting. In cilta-cel patients response rates were higher and atypical neurotoxicities/infections more frequent. Peak CAR T counts were significantly higher in cilta-cel patients, driven by CD4<sup>+</sup> CAR expansion, correlating with clinical responses. Expansion of cilta-cel cells was associated with higher CAR and CD27 expression while, in contrast to ide-cel, there was no correlation between TIM3 expression and CAR T proliferation. Cilta-cel CAR T expansion was followed by a CAR-specific switch from proliferation-associated genes to genes/surface markers indicating effector/memory function. The longer persistence of cilta-cel CAR T was associated with increased IL-7R expression; in vitro data showed persistent antigen-independent activation and higher metabolic activity of cilta-cel vs. ide-cel CAR T. Among cilta-cel-treated patients experiencing atypical neurotoxicities, central nervous system (CNS)-infiltrating, effector-type CAR T presented a distinct inflammatory phenotypic/cytokine-expression profile. This in-depth biomonitoring report following real-world cilta-cel or ide-cel highlights intrinsic biological differences between BCMA-targeting CAR T products, potentially explaining differences in clinical activity and toxicity. Our findings may guide optimization of cellular immunotherapy strategies in MM.</p>

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Immune correlates of anti-BCMA CAR-T products idecabtagene vicleucel and ciltacabtagene autoleucel in a real-world cohort of patients with multiple myeloma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月4日

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  • Djordje Atanackovic,
  • Tim Luetkens,
  • Dina Schneider,
  • Peirong Hu,
  • Xu Wang,
  • Amol C. Shetty,
  • Luke Tallon,
  • Imari Patel,
  • Rohan Singh,
  • Etse Gebru,
  • Rediet Mulatu,
  • Destiny Omili,
  • Daniel Yamoah,
  • Xiaoxuan Fan,
  • Aerielle Matsangos,
  • Patricia Lesho,
  • Kenneth A. Dietze,
  • Ariel A. Fromowitz,
  • Kim G. Hankey,
  • Saurabh Dahiya,
  • Jean A. Yared,
  • Nancy M. Hardy,
  • Rima Koka,
  • Michael E. Kallen,
  • Ashraf Badros,
  • Aaron P. Rapoport,
  • Mehmet H. Kocoglu

摘要

We performed the first in-depth, comparative and prospective biomonitoring of Multiple Myeloma (MM) patients (N = 39) receiving ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel (ide-cel) chimeric antigen receptor T cells (CAR T) in the real-world setting. In cilta-cel patients response rates were higher and atypical neurotoxicities/infections more frequent. Peak CAR T counts were significantly higher in cilta-cel patients, driven by CD4+ CAR expansion, correlating with clinical responses. Expansion of cilta-cel cells was associated with higher CAR and CD27 expression while, in contrast to ide-cel, there was no correlation between TIM3 expression and CAR T proliferation. Cilta-cel CAR T expansion was followed by a CAR-specific switch from proliferation-associated genes to genes/surface markers indicating effector/memory function. The longer persistence of cilta-cel CAR T was associated with increased IL-7R expression; in vitro data showed persistent antigen-independent activation and higher metabolic activity of cilta-cel vs. ide-cel CAR T. Among cilta-cel-treated patients experiencing atypical neurotoxicities, central nervous system (CNS)-infiltrating, effector-type CAR T presented a distinct inflammatory phenotypic/cytokine-expression profile. This in-depth biomonitoring report following real-world cilta-cel or ide-cel highlights intrinsic biological differences between BCMA-targeting CAR T products, potentially explaining differences in clinical activity and toxicity. Our findings may guide optimization of cellular immunotherapy strategies in MM.