编者按：细胞治疗作为突破性治疗手段，已在多种恶性血液病中展现出显著疗效。然而，在慢性淋巴细胞白血病（CLL）中，其应用仍面临一定挑战。由中国研究型医院学会细胞研究与治疗专业委员会、北京大学人民医院雄安医工交叉转化研究院主办的“2025中国研究型医院学会细胞治疗及生物医学前沿学术会议”于2025年10月31日-11月1日在雄安盛大举行。会上，里尔大学医院Micha SROUR教授带来了“Advances in Cellular Therapy for CLL”（细胞疗法在CLL中的最新进展）的专题报告，系统阐述了该领域的最新研究成果与临床探索。与会现场，《肿瘤瞭望-血液时讯》特邀Micha SROUR教授接受采访，围绕CAR-T细胞疗法在CLL中的应用现状、面临挑战及未来发展方向进行了深入解读。
Micha SROUR教授：截至目前，TRANSCEND 0004研究的最新数据已公布。该研究结果促使FDA批准了自体CD19靶向嵌合抗原受体（CAR）T细胞疗法lisocabtagene maraleucel（liso-cel）用于慢性淋巴细胞白血病（CLL）患者的治疗，但其在欧洲及其他地区尚未获批。
对于经B淋巴细胞瘤-2（BCL-2）抑制剂及布鲁顿酪氨酸激酶（BTK）抑制剂治疗后复发的CLL患者，目前可选择的治疗方案仍然有限。为了满足这一人群的临床需求，研究者们持续探索新的治疗策略，其中CAR-T细胞疗法被寄予厚望。
然而，CAR-T疗法在CLL中的应用仍面临显著挑战。与其他B细胞恶性肿瘤不同，CLL患者的CAR-T细胞扩增不足是影响疗效的关键问题之一。针对这一难题，法国Hutchinson癌症研究中心的Jordan Gauthier团队进行了深入研究，尝试通过在单采前及CAR-T细胞回输后联合使用伊布替尼来改善CAR-T细胞的扩增能力。研究结果显示，该策略可显著提高CAR-T细胞的扩增水平和扩增速度，并提升患者的总体缓解率。然而，与弥漫性大B细胞淋巴瘤（DLBCL）中可观察到的疗效“平台期”相比，CLL患者仍未达到类似的持久反应，这意味着CAR-T疗法在CLL中的疗效仍有待进一步优化。
CLL是一种治疗难度较高的疾病，尤其对于携带TP53突变，或对BTK抑制剂、BCL-2抑制剂产生耐药的患者，临床应对更为棘手。令人欣慰的是，新一代BTK抑制剂的出现为这一问题带来了新的解决思路。正如帕纳替尼（ponatinib）成功应对慢性髓性白血病（CML）中的T315I突变一样，未来创新型BTK抑制剂有望在克服CLL耐药突变方面发挥重要作用。
总体来看，CAR-T疗法在CLL治疗中仍未展现出理想的疗效，短期内也难以在欧洲获得批准。与此同时，双特异性抗体等新型免疫疗法正逐步进入CLL领域，展现出良好的发展前景。随着多种创新疗法的不断涌现，未来有望在部分患者中减少对细胞治疗的依赖。
此外，对于部分年轻、身体状况良好且携带TP53突变或del（17p）异常的患者，异基因造血干细胞移植仍可作为潜在的治疗选择，为患者带来更长期的生存获益。
Prof. Micha SROUR: As of now, the latest data from the TRANSCEND 0004 study have been released. These results led to FDA approval of the autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel) for the treatment of patients with chronic lymphocytic leukemia (CLL). However, it has not yet been approved in Europe or other regions.
For CLL patients who relapse after treatment with B-cell lymphoma-2 (BCL-2) inhibitors and Bruton tyrosine kinase (BTK) inhibitors, therapeutic options remain extremely limited. To address this unmet clinical need, researchers continue to explore novel strategies, with CAR-T cell therapy holding considerable promise.
Nevertheless, the application of CAR-T therapy in CLL faces significant challenges. Unlike in other B-cell malignancies, insufficient CAR-T cell expansion in CLL patients is a key factor limiting efficacy. To tackle this issue, the team led by Jordan Gauthier at the Hutchinson Cancer Research Center in France conducted in-depth research, attempting to enhance CAR-T cell expansion by combining ibrutinib administration before apheresis and after CAR-T cell infusion. The results demonstrated that this approach significantly improved CAR-T cell expansion levels and rates, as well as overall response rates in patients. However, compared to the durable response “plateau” observed in diffuse large B-cell lymphoma (DLBCL), CLL patients have not yet achieved similar sustained responses, indicating that further optimization of CAR-T therapy efficacy in CLL is still required.
CLL is a highly refractory disease, particularly in patients harboring TP53 mutations or developing resistance to BTK or BCL-2 inhibitors, where clinical management is especially challenging. Encouragingly, the emergence of next-generation BTK inhibitors offers new solutions to this problem. Just as ponatinib successfully overcomes the T315I mutation in chronic myeloid leukemia (CML), innovative BTK inhibitors in the future are expected to play a critical role in addressing drug-resistant mutations in CLL.
Overall, CAR-T therapy has yet to demonstrate ideal efficacy in CLL treatment and is unlikely to gain approval in Europe in the near term. Meanwhile, novel immunotherapies such as bispecific antibodies are gradually entering the CLL treatment landscape, showing promising prospects. With the continuous emergence of various innovative therapies, it is anticipated that reliance on cellular therapies may be reduced in certain patient populations in the future.
Additionally, for select young patients in good physical condition with TP53 mutations or del(17p) abnormalities, allogeneic hematopoietic stem cell transplantation remains a viable treatment option, potentially offering longer-term survival benefits.
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