摘要：2024年11月14日至17日，国际细胞与免疫治疗（CTI）大会在中国杭州盛大举行，汇聚了全球细胞治疗和免疫治疗领域的顶尖专家、学者和行业领袖。此次大会不仅是一个学术交流的国际平台，更是一个展示最新科研成果、推动领域发展的重要窗口。会议期间，《肿瘤瞭望-血液时

2024年11月14日至17日，国际细胞与免疫治疗（CTI）大会在中国杭州盛大举行，汇聚了全球细胞治疗和免疫治疗领域的顶尖专家、学者和行业领袖。此次大会不仅是一个学术交流的国际平台，更是一个展示最新科研成果、推动领域发展的重要窗口。会议期间，《肿瘤瞭望-血液时讯》特别邀请到法国国家卫生局主席、法国南特大学René Gauducheau癌症中心主任Jean-Luc Harousseau教授，为我们详细阐述了目前免疫治疗的优势与局限性，以及其应用现状与前景。现将访谈精髓整理成文，以飨读者，共同探索多发性骨髓瘤免疫治疗的未来之路。

Q1

免疫治疗与传统治疗相比，有哪些优势和局限性？在实际应用中，如何平衡这些治疗手段？

Jean-Luc Harousseau教授：免疫治疗之所以与传统治疗存在差异，是因为免疫治疗专注于骨髓瘤细胞表面的特定分子，相较于其他治疗手段展现出更高的特异性。鉴于免疫治疗包含四种不同类型，因此全面评估其总体疗效颇具挑战性。其中，靶向CD38的单克隆抗体（mAbs）是重要的一环。目前，有两种极为活跃的单克隆抗体正在与标准疗法联合应用，广泛适用于年轻及老年患者。

另一种治疗方法是抗体-药物偶联物（ADCs），以belantamab mafodotin为代表，该药物具有良好的耐受性，但会引发一种特殊毒性——角膜毒性。然而，在CAR-T细胞和双特异性抗体这两种新型免疫疗法面前，其疗效略显逊色。CAR-T细胞作为多发性骨髓瘤领域的开创性疗法，在复发/难治性多发性骨髓瘤治疗中展现出卓越活性。例如，西达基奥仑赛（Cilta-cel）在经多重预处理的患者中实现了98%的总缓解率，其中82%的患者达到完全缓解，这一疗效堪称前所未有。CAR-T细胞的毒性特征独特，主要包括细胞因子释放综合征和神经毒性。尽管在多发性骨髓瘤患者中，这些不良事件较为常见，但通常程度较轻且可逆。

此外，双特异性抗体同样展现出与CAR-T细胞相当的活性，在经多重预处理的患者中应答率约为60%至65%，这一数据显著高于ADCs的30%缓解率。双特异性抗体的毒性与CAR-T细胞相似，但程度相对较轻。与CAR-T细胞相比，双特异性抗体引发的细胞因子释放综合征和神经毒性症状显著减轻。然而，双特异性抗体面临的一个特定挑战是感染发生率较高，这些感染可能较为严重，甚至在长期治疗过程中持续存在。

Oncology Frontier-Hematology Frontier：Compared to traditional treatments, what are the strengths and limitations of immunotherapy? How do you balance these treatment modalities in clinical practice?

Dr.Jean-Luc Harousseau：These are different approaches because immunotherapy targets molecules on the surface of myeloma cells and are more specific than other treatments. It's difficult to have an overall response because there are four types of immunotherapy. There are naked antibodies targeting CD38. So, there are two mAbs (monoclonal antibodies), which are very active and are currently given in combination with standard treatments, both in young and elderly patients.

Second are the antibody-drug conjugates (ADCs) belantamab mafodotin, which are well-tolerated as well with a very special toxicity, which is corneal toxicity. But the efficacy of this antibody is less important than the other two new immunotherapies, which are CAR-T cells and bispecific. CAR-T cells were the first to be introduced in multiple myeloma. They are extraordinarily active in relapsed/refractory multiple myeloma. For instance, cilta-cel induce a 98% response rate in heavily pretreated patients, with 82% complete response—that is really unprecedented. The toxicity of CAR-T cells is quite different. It usually includes cytokine release syndrome and neurotoxicity. But in multiple myeloma, these adverse events are frequent, but usually mild and reversible.

Finally, there are bispecific antibodies, which are almost as active as CAR-T cells, probably with a 60% to 65% response rate in heavily pretreated patients. This is more than the ADCs, which have only a 30% response rate. The toxicity of bispecific antibodies is almost the same as that of CAR-T cells, but less pronounced. The severity of cytokine release syndrome and neurotoxicity is much milder with bispecific antibodies than with CAR-T cells. The specific problem with bispecific antibodies is the incidence of infections, which can be severe and can be seen even for long-term treatments.

Q2

您认为在新诊断的多发性骨髓瘤患者的免疫治疗中，哪些免疫疗法展现出了最具潜力的治疗效果？是否有特定的患者群体受益更多？

Jean-Luc Harousseau教授：目前，针对新诊断的多发性骨髓瘤患者，仅采用一种免疫疗法，即抗CD38抗体疗法，该疗法广泛适用于老年及年轻患者群体。临床实践中，将达雷妥尤单抗（daratumumab）或伊沙妥昔单抗（isatuximab，或称艾沙妥昔单抗）与标准疗法（涵盖来那度胺联合地塞米松的RD方案，以及硼替佐米、来那度胺与地塞米松联用的VRd方案）相结合，已证实能显著提升患者的完全缓解（CR）率，有效改善10^-5水平的微小残留病（MRD）阴性率，并延长患者的无进展生存期（PFS）。

然而，关于其他免疫疗法，如CAR-T细胞疗法或双特异性抗体疗法，在多发性骨髓瘤治疗中的潜在作用，目前尚存争议。这一问题的复杂性在于，达雷妥尤单抗和伊沙妥昔单抗已展现出卓越的临床疗效，因此它们可能仅在特定情境下被考虑使用，例如针对具有极高细胞遗传学风险的患者、对达雷妥尤单抗联合标准疗法反应不佳的患者，或早期复发的患者。

尽管如此，自体移植后的巩固治疗和维持治疗仍被视为一种有效的治疗策略，其同样适用于老年患者。然而，这类治疗周期漫长，可能伴随不良事件的发生，且治疗费用高昂。因此，一个亟待解决的问题是，CAR-T细胞疗法或双特异性抗体疗法是否有望成为移植后老年及年轻患者巩固治疗或维持治疗的替代方案。这一问题的探讨对于优化多发性骨髓瘤的治疗策略具有重要意义。

Oncology Frontier-Hematology Frontier：Which immunotherapies do you believe have shown the most potential in treating newly diagnosed multiple myeloma patients? Can immunotherapy positively impact the long-term survival and quality of life for newly diagnosed multiple myeloma patients? Are there specific patient populations that benefit more?

Dr.Jean-Luc Harousseau：Currently, the treatment of a newly diagnosed multiple myeloma uses only one type of immunotherapy, which is the anti-CD38 antibody,both in elderly and young patients. The combination of daratumumab or isatuximab with the standard of care, which includes Revlimid+dexamethasone(RD)、Velcade+Revlimid+dexamethasone(VRd)， does improve the complete response (CR) rates,does improve the the rate of minimal residual disease (MRD) negativity at the level of 10^-5, and does improve progression-free survival (PFS).

So, is there a role for other immunotherapies, like CAR-T cells or bispecifics? It's not easy to answer this question because the results are so good,with daratumumab or isatuximab that probably they will be used only in some specific indications. For instance, in patients with very high-risk cytogenetics, or patients who don't respond well to daratumumab plus standard of care,or patients who relapse early.

But maybe there could be an indication for consolidation and maintenance therapy after autologous transplantation, currently. And that's true for elderly patients as well. The treatment is very prolonged, which can induce adverse events and is expensive. So, one question is whether, for instance, CAR-T cells or bispecifics could replace consolidation or maintenance therapy, both in elderly and younger patients after transplantation.

Q3

在新诊断的多发性骨髓瘤患者的免疫治疗中，是否存在一些挑战或难点？您认为应该如何克服这些挑战，以进一步提高免疫治疗的效果？

Jean-Luc Harousseau教授：我认为，当前医疗领域面临的一项重大挑战在于：现有治疗方案已展现出极佳的疗效，在此背景下，对于那些在接受标准治疗联合达雷妥尤单抗或伊沙妥昔单抗后预后情况良好的患者，我们是否仍有必要引入CAR-T细胞疗法或双特异性抗体治疗，这成为了一个值得深思的问题。

对于高风险患者群体而言，CAR-T细胞疗法及双特异性抗体无疑具有潜在的应用价值。同时，近期涌现的双特异性抗体组合疗法可能为罹患如伴发髓外病变的多发性骨髓瘤等严重疾病的患者带来新的希望。

此外，如我先前所述，一个更为核心的问题在于如何精准识别哪些患者能够真正从这种新型免疫疗法中获益，毕竟当前的治疗方案已经取得了令人瞩目的疗效。这就要求我们在疗效、毒性和成本之间寻求一个合理的平衡点。值得注意的是，长期使用如达雷妥尤单抗等治疗药物，其费用可能相当高昂。而在西方国家，尽管CAR-T细胞疗法仅需单次治疗，但其价格同样不菲。因此，我们面临的一个关键抉择是，是否应考虑在限定时间内使用双特异性抗体，以期在缩短治疗周期、减轻副作用的同时，也能有效控制长期治疗的成本。

Oncology Frontier-Hematology Frontier：Are there any challenges or difficulties in the immunotherapy of newly diagnosed multiple myeloma patients? How do you think we can overcome these challenges to further improve the effectiveness of immunotherapy?

Dr.Jean-Luc Harousseau：I think that the most important challenge is that the result of current treatment is very good. Do we really need CAR-T cells or bispecifics in patients who have such a good prognosis with standard treatment plus daratumumab or isatuximab? The challenges are for high-risk patients for whom CAR-T cells or bispecifics could be useful. And for recent combinations of bispecifics could be useful in patients with very severe disease like multiple myeloma with extramedullary disease. This is a very important challenge.

Otherwise, as I said, the question is really to define which patients should benefit from this new earth therapy, knowing that the results of the current treatment are so good. It will be a balance of efficacy, toxicity, but also of cost. Because long-term treatment with standards like daratumumab might be very expensive. CAR-T cells in Western countries are very expensive, but it's also a single shot. And the question will be whether to use bispecifics for a limited period of time, trying to reduce the duration, the side effects, and the cost of prolonged therapy.

总 结

通过Jean-Luc Harousseau教授的精彩分享，我们认识到多发性骨髓瘤免疫治疗领域所取得的显著进展与挑战。免疫治疗以其高度的特异性，为多发性骨髓瘤患者带来了新的治疗希望，尤其是CAR-T细胞疗法和双特异性抗体等新兴疗法，在复发/难治性多发性骨髓瘤患者中展现出了卓越疗效。然而，如何在现有疗效优越的治疗方案的基础上，合理选择免疫疗法，平衡疗效、毒性和成本，成为当前面临的重要课题。对于新诊断的多发性骨髓瘤患者，抗CD38抗体疗法已广泛应用于临床实践，但其他免疫疗法的应用仍需谨慎评估，尤其是在特定患者群体中的疗效与安全性。未来，随着免疫治疗的不断发展，我们期待能够精准识别获益患者，优化治疗策略，为患者带来更长久的生存与更高的生活质量。

来源：肿瘤瞭望