编者按：一年一度的欧洲血液学协会年会（EHA）于近日在德国法兰克福以线上线下相结合的形式顺利举行。作为欧洲血液学领域规模最大的国际性会议，EHA大会全面分享了各种科学主题、临床和基础研究，涵盖良性和恶性血液学，并讨论血液学领域的最新进展。在本次EHA大会上，来自美国Atrium Health Levine Cancer Institute的Ryan Jacobs教授团队的一项研究（abstract S224）探索了TNB-486（靶向CD19/CD3）在复发/难治滤泡淋巴瘤治疗中的价值，取得了较为不俗的疗效结果。为此，《肿瘤瞭望》在现场特邀采访了Ryan Jacobs教授并详细解读了滤泡淋巴瘤及弥漫大B细胞淋巴瘤治疗方面的新进展。

Ryan Jacobs教授：确实，在本次EHA大会上有相关研究报道了该联合方案在滤泡淋巴瘤（FL）治疗中的有效性，双特异性抗体Epcoritamab+来那度胺+利妥昔单抗尤其是一组非常令人鼓舞的三联方案。首先，来那度胺+利妥昔单抗（R2方案）可能是目前滤泡淋巴瘤二线标准治疗中接受度最高的一种方案，近来更新的研究数据显示，尽管R2方案的无进展生存（PFS）可能大约为2年多，但是至下次治疗的间隔时间（TTNT）超过了70个月，因此R2方案本身就是一项非常有效的治疗方法，而在此基础上联合一种双特异性抗体能在一定程度上增强来那度胺（一种免疫调节剂）的免疫介导效应，因此该三联方案是合理的，在相关研究中也确实显示出较高的客观缓解率（ORR）和完全缓解率（CR）。

 

Pro.Ryan Jacobs:Yes，this efficacy was reported in this meeting，specifically looking at the Epcoritamab，Revlimid，Rituximab，triplet.it’s an exciting triplet combination.Revlimid plus Rituximab is the current probably most well accepted standard for second line management of follicular lymphoma，and recent updates have shown that although the PFS is perhaps only a bit more over 2 years，the time to next treatment is over 70 months.So it is a an effective treatment in its own right.adding a bispecific antibody seems to make sense，Given that Revlimid is an immunomodulatory agent being able to potentiate that immune modulatory response with the addition of a bispecific antibody，scientifically makes sense.And we are seeing that the data reported with the high overall response rates and high Complete remission rates.

 

Ryan Jacobs教授：这是一项I期的首次人类临床试验，该药（TNB-486）在临床试验中登记用于不同亚型的非霍奇金淋巴瘤（NHL）治疗，本研究则是报道了其对于滤泡淋巴瘤（FL）患者的疗效，尤其是TNB-486剂量≧2.4mg的患者。尽管，本研究中纳入的滤泡淋巴瘤患者均为复发或难治性，既往接受的平均治疗线数为3线，但仍显示出很高的总体有效率，TNB剂量≧2.4mg患者的完全缓解率（CR）达到了91%，这还仅是单药治疗的效果，TNB-486带来了令人兴奋的疗效进展，而这种单药疗效既往仅在靶向CD20/CD3的双特异性抗体中达到，例如Epcoritamab、Glofitamab以及Mosunetuzumab。另外，针对于弥漫大B细胞淋巴瘤（DLBCL）的治疗，靶向CD19的单抗Tafasitamab、靶向CD19的单抗与细胞毒药物偶联成的抗体药物偶联物（ADC）Loncastuximab tesirine也有不俗疗效，但仅限于DLBCL。而针对于滤泡淋巴瘤而言，唯一能直接靶向CD19的治疗药物只有CAR-T，但不幸的是，很多FL患者并不符合CAR-T治疗的条件，或者其地理位置不接近CAR-T治疗中心，或因其他原因（经济因素等）无法实施。因此，我们非常期待探寻到一种能靶向CD19的双特异性抗体，TNB-486（靶向CD19/CD3）已经显示出良好的单药疗效，而且治疗耐受性极佳，非常期待TNB-486与其它药物的联合应用，这对于既往接受过多种CD20单抗治疗后复发的滤泡淋巴瘤而言，无疑是令人鼓舞的治疗选择。

 

Pro.Ryan Jacobs:Our study was a phase one first in human study.It is being investigated in several different Non-Hodgkin lymphoma subtypes.But today we just reported on the follicular lymphoma subgroup.And specifically，we were looking at patients that had received a dose of at least 2.4 milligrams.Now，for those patients in our study that were highly relapsed/refractory with a median number of treatments of three，we did see high overall response in high Complete remission rates with 91%of patients when treated with at least 2.4 milligrams，and this is what just a single agent.TNB-486 is an exciting step-forward.Right now，we only have bispecifics that are CD20/CD3 bispecifics，such as Epcoritamab，Glofitamab and Mosunetuzumab.And we have monoclonal antibodies to CD19 like Tafasitamab and anti-CD19，antibody-drug conjugate like Loncastuximab tesirine，but those are only available in diffuse large B cell lymphoma.For follicular lymphoma patients，in particularly，the only CD19 directed therapy that we have available in the United States is CAR-T cell therapy.There are many patients that unfortunately are not eligible for CAR-T，or are not near a CAR-T center or would find all of them goes into having to be treated with CAR-T and in-patient monitoring，just something they’re not able to do.So we would like to be able to have the ability to target CD 19 with a bispecific，The TNB-486 is shown to be effective as a single agent，it’s also been shown to be very well tolerated.So I think there is also a lot of excitement that we could combine this with other，and this is very exciting for follicular lymphoma patients that have seen generally multiple CD20 directed therapies by the time they’ve had multiple recurrence.

 

Ryan Jacobs教授：是的，Polatuzumab vedotin已经在美国被FDA获批与利妥昔单抗、环磷酰胺、多柔比星及泼尼松（Pola-R-CHP）联合用于弥漫大B细胞淋巴瘤（DLBCL）的一线治疗，并替代R-CHOP方案成为IPI≧2分的进展期DLBCL的标准方案。在POLARIX研究中显示，在与R-CHOP方案头对头的比较中，Pola-R-CHP能使患者的2年无进展生存（PFS）率提升达6%。Polatuzumab vedotin是一类靶向CD79b并与化疗药物偶联的抗体药物偶联物（ADC），即便单药也在复发性DLBCL患者的治疗中展现出一定的疗效，其与R-CHP联合组成Pola-R-CHP并未增加治疗的毒副作用，神经学毒性也没有显著增加，如上所述，2年PFS提高了6%。目前正在开展III期临床试验来进一步探讨和验证该联合方案较之于R-CHOP方案的优势。

 

Pro.Ryan Jacobs:Yes，Polatuzumab has recently achieved FDA approval in the United States to be combined with Rituximab，Cyclophosomide，Doxorubicin and Prednisone or what we refer to as Pola-R-CHP and it replaced R-CHOP as the standard of care for patients with an IPI of at least two or greater with advanced DLBCL，it achieved this approval with a 6%improvement in Progression Free Survival when compared head to head with R-CHOP in the POLARIX study.Polatuzumab is an antibody-drug conjugate that targets CD79b and it has a chemotherapy linker，It has been shown even as a single agent to have efficacy in relapsed DLBCL.Combining it in Pola-R-CHP did not appear to add any toxicity，particularly no really significant increases in neuropathy.We are seeing improvement in PFS is 6%，so we now finally have a phase three study of a combination treatment going up against R-CHO where we have superiority.

 

Ryan Jacobs教授

美国Atrium Health Levine Cancer Institute