血液国际谈丨Norbert Claude Gorin教授:自体移植结合免疫疗法,有望优化AML治疗格局

文摘   2024-10-28 17:20   北京  


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近日,中国医师协会第十一届中法血液学学术会议在天津顺利召开,吸引到数百名国内外血液学领域的权威专家和学者齐聚一堂。会议期间,《肿瘤瞭望-血液时讯》特邀巴黎圣安东尼医院、法国国家医学科学院院士、中国工程院外籍院士Norbert Claude Gorin教授就自体移植在急性髓系白血病(AML)治疗中的角色演变和免疫疗法在AML治疗中的挑战与潜力进行了探讨。现将精粹整理成文,以飨读者。

《肿瘤瞭望-血液时讯》:


自体移植在AML治疗中的历史地位至关重要,但随着新药和免疫疗法的涌现,您认为自体移植的未来角色将如何演变?

Norbert Claude Gorin教授:在AML的治疗中,异基因造血干细胞移植(allo-HSCT)通常被认为是最有效的缓解后治疗方法,主要依赖于移植物介导的抗肿瘤效应,即移植物抗白血病效应(GVL),通过供者T细胞与肿瘤表面抗原发生免疫应答来清除白血病细胞,但该过程具有一定的毒性。为了减轻这种毒性,有时需要降低治疗的强度。


相比之下,自体造血干细胞移植(ASCT)具有不受供者限制、不发生移植物抗宿主病(GVHD)、移植相关死亡率低等优势,然而其抗肿瘤效果相对较弱。随着新药和免疫疗法的涌现,ASCT的未来角色可能会发生演变。一方面,ASCT可以作为不适合allo-HSCT患者的一种治疗选择。对于那些无法找到合适供者或难以承受allo-HSCT高强度治疗的患者,ASCT 仍然具有一定的价值。另一方面,结合免疫治疗有望弥补ASCT抗肿瘤效果较弱的不足,增强ASCT后的抗肿瘤免疫反应。目前,ASCT结合免疫疗法的策略正在探索中,旨在实现与allo-HSCT相同的治疗效果的同时减少副作用,提升患者生活质量。这种策略的探索和优化无疑是未来AML治疗研究的重要方向之一。

总之,新药和免疫疗法的涌现为AML治疗带来了新的机遇和挑战,自体移植在特定患者群体中仍有其存在的价值,并且通过与新兴疗法的结合,其未来可能会在AML治疗中继续发挥重要作用。

(上下滑动查看英文原文)

Oncology Frontier-Hematology Frontier: Given the historical significance of autologous transplantation in AML treatment, how do you envision the future role of this approach evolving amidst the emergence of novel drugs and immunotherapies?
Dr. Norbert Claude Gorin: In the treatment of acute myeloid leukemia , allogeneic hematopoietic stem cell transplantation is often considered the most effective post-remission treatment method. It primarily relies on the graft-versus-leukemia effect, which involves an immune response by donor T cells against tumor surface antigens to eliminate leukemia cells. However, this process can be toxic, and sometimes the intensity of the treatment needs to be reduced to mitigate this toxicity.
In contrast, autologous hematopoietic stem cell transplantation has the advantages of no donor restrictions, no graft-versus-host disease , and low transplant-related mortality. However, its anti-tumor effect is relatively weak. With the emergence of new drugs and immunotherapies, the future role of ASCT may evolve. On one hand, ASCT can serve as a treatment option for patients who are not suitable for allo-HSCT. For those who cannot find a suitable donor or cannot tolerate the high-intensity treatment of allo-HSCT, ASCT still has value. On the other hand, combining immunotherapy is expected to make up for the weakness of ASCT's anti-tumor effect and enhance the anti-tumor immune response after ASCT. Currently, strategies combining ASCT with immunotherapy are being explored, aiming to achieve the same therapeutic effects as allo-HSCT while reducing side effects and improving patients' quality of life. The exploration and optimization of this strategy are undoubtedly one of the important directions for future AML treatment research.
In summary, the emergence of new drugs and immunotherapies has brought new opportunities and challenges to AML treatment. Autologous transplantation still has its value in specific patient populations, and by combining with emerging therapies, it may continue to play an important role in AML treatment in the future.


《肿瘤瞭望-血液时讯》:


免疫疗法,如CAR-T细胞疗法或免疫检查点抑制剂,在复兴自体移植作为AML治疗手段方面有哪些潜在的优势或挑战?

Norbert Claude Gorin教授:免疫疗法的优势在于,免疫检查点抑制剂如抗CD47的单克隆抗体能够使巨噬细胞杀伤AML细胞,这是一种通过阻断免疫抑制信号来增强免疫系统对肿瘤细胞的攻击的策略。CAR-T细胞疗法则通过基因工程改造患者的T细胞,使其能够识别并杀死特定的癌细胞,包括AML细胞。这些治疗方法能够提供更为精准的治疗,减少对正常细胞的损害,并且有可能实现长期的疾病控制。


同时,免疫疗法在AML治疗中面临着不容忽视的挑战。挑战之一是寻找合适的靶点,因为AML细胞上的抗原可能也在正常造血干细胞上表达,这可能导致治疗相关的毒性。其次是免疫逃逸,肿瘤细胞可能会下调靶抗原的表达来逃避免疫系统的攻击。此外,免疫疗法可能会引起严重的副作用,如细胞因子释放综合征(CRS)和免疫效应细胞相关神经毒性综合征(ICANS),需要密切监测和妥善管理。

总而言之,免疫疗法在AML治疗中表现出巨大的潜力,但同时也需要克服一些挑战。未来的研究可能会集中在开发更安全、更有效的免疫治疗策略,以及如何将这些疗法与其他治疗手段(如化疗等)结合起来,以提高AML患者的治疗效果和生活质量。

(上下滑动查看英文原文)

Oncology Frontier-Hematology Frontier: What are the potential advantages or challenges of immunotherapies such as CAR-T cell therapy or immune checkpoint inhibitors in reviving autologous transplantation as a treatment modality for AML?
Dr. Norbert Claude Gorin: Immunotherapy holds significant promise in the treatment of acute myeloid leukemia , with immune checkpoint inhibitors such as anti-CD47 monoclonal antibodies enabling macrophages to target and eliminate AML cells. This approach enhances the immune system's attack on cancer cells by blocking immunosuppressive signals. CAR-T cell therapy involves genetically engineering a patient's T cells to recognize and destroy specific cancer cells, including those of AML. These treatments offer precision medicine, reducing damage to healthy cells and potentially leading to long-term disease control.
However, immunotherapy in AML faces considerable challenges. One is identifying suitable targets, as antigens on AML cells may also be expressed on normal hematopoietic stem cells, risking treatment-related toxicity. Secondly, immune evasion can occur as tumor cells may downregulate the expression of target antigens to escape immune attacks. Additionally, immunotherapy can cause severe side effects, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome , which require close monitoring and proper management.
In summary, while immunotherapy shows tremendous potential in AML treatment, it also needs to overcome several challenges. Future research may focus on developing safer and more effective immunotherapeutic strategies and how to combine these with other treatment modalities, such as chemotherapy, to improve treatment outcomes and quality of life for AML patients.


《肿瘤瞭望-血液时讯》:


在结合免疫疗法与自体移植的策略上,有哪些临床试验正在进行,这些试验的结果对AML治疗有何预期影响?

Norbert Claude Gorin教授:据我所知,一项单臂II期研究MyloFrance-1,评估了吉妥珠单抗(Gemtuzumab ozogamicin)单药治疗首次复发CD33+成人AML患者的疗效。研究数据显示,在中位年龄为64岁(22-80岁)的57例患者中,患者的完全缓解率(CR)为26%,中位无复发生存期(RFS)为11.6个月。


未来,随着更多临床试验的开展和结果的公布,我们可以期待免疫疗法与自体移植联合的治疗策略在AML治疗中不断优化和完善,为AML患者带来更多的希望和更好的治疗效果。

(上下滑动查看英文原文)

Oncology Frontier-Hematology Frontier: What clinical trials are currently underway that combine immunotherapy with autologous transplantation strategies, and what are the anticipated impacts of these trial results on AML treatment?
Dr. Norbert Claude Gorin: As far as I know, in the treatment of acute myeloid leukemia , the MyloFrance-1 single-arm phase II study evaluated the efficacy of gemtuzumab ozogamicin monotherapy in adult patients with CD33-positive AML at first relapse. The study involved 57 patients with a median age of 64 years (ranging from 22 to 80 years), and the complete remission rate was 26%, with a median relapse-free survival of 11.6 months. These results suggest that gemtuzumab ozogamicin can be an effective treatment option for this patient population .
As more clinical trials are conducted and their results are published, we can anticipate that the therapeutic strategy combining immunotherapy with autologous transplantation will continue to be optimized and refined in the treatment of AML. This approach holds the potential to offer more hope and better therapeutic outcomes for AML patients.


专家简介


Norbert Claude Gorin教授

巴黎索邦大学血液学和细胞治疗教授

欧洲血液和骨髓移植学会(EBMT)全球委员会主席

法国国家医学科学院院士

中国工程院2023年外籍院士


(来源:《肿瘤瞭望–血液时讯》编辑部)


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