T cell dysfunction associated with repeated CAR-T cell manufacturing failure following prolonged bispecific antibody exposure: a case report

IF 0.8 Q4 HEMATOLOGY

Leukemia Research Reports Pub Date : 2026-01-01 Epub Date: 2026-09-16 DOI:10.1016/j.lrr.2026.100611

Skylar J.W. Henry, Kirsten Pfeffer, Kevin G. Shim, Erin W. Meermeier, Fan Feng, Julia E. Wiedmeier, Saurabh Chhabra, P. Leif Bergsagel, Rafael Fonseca, Alex M. Wonnaparhown, Michael P. Gustafson

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Abstract

Overview

We describe a patient with two consecutive manufacturing failures after prolonged bispecific antibody treatment in which longitudinal immune phenotyping and functional assays were performed to investigate potential mechanisms.

Background

CAR-T cell therapy and bispecific antibodies (BsAb) have significantly improved outcomes in relapsed/refractory multiple myeloma (r/rMM), yet the optimal treatment sequence remains unclear, particularly regarding the impact of prior BsAb exposure on downstream CAR-T manufacturability.

Case Presentation

A 72-year-old man with r/rMM had two CAR-T cell manufacturing failure events following multiple therapies including an FcRL5 × CD3 bispecific antibody. Both collections yielded an insufficient CAR-T cell dose. Longitudinal immune phenotyping revealed markers of T cell dysfunction, including loss of CCR7, CD27, and CD28, alongside severely impaired TCR-driven proliferation with preserved interleukin-2 responsiveness.

Conclusion

These findings link profound T cell dysfunction with repeated CAR-T cell manufacturing failures and suggest that pre-leukapheresis immune phenotyping may identify patients at risk for manufacturing failure.

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长时间双特异性抗体暴露后与重复CAR-T细胞制造失败相关的T细胞功能障碍：一例报告

我们描述了一位在长时间双特异性抗体治疗后连续两次制造失败的患者，其中进行了纵向免疫表型和功能分析以研究潜在的机制。CAR-T细胞疗法和双特异性抗体（BsAb）显著改善了复发/难治性多发性骨髓瘤（r/rMM）的治疗结果，但最佳治疗顺序尚不清楚，特别是关于先前暴露于BsAb对下游CAR-T可制造性的影响。病例介绍：一名72岁的r/rMM患者在接受包括FcRL5 × CD3双特异性抗体在内的多种治疗后出现了两次CAR-T细胞制造失败事件。两种收集的CAR-T细胞剂量都不足。纵向免疫表型揭示了T细胞功能障碍的标志物，包括CCR7、CD27和CD28的缺失，以及tcr驱动的增殖严重受损，同时保留了白细胞介素-2反应性。这些发现将严重的T细胞功能障碍与重复的CAR-T细胞制造失败联系起来，并提示白血病前免疫表型可以识别有制造失败风险的患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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