徐医附院细胞研究和转化医学中心副主任
徐医附院血液科科副主任,淋巴瘤病区主任
中华医学会血液学分会淋巴细胞疾病学组委员
中国抗癌协会淋巴瘤专委会委员
中国EBV相关疾病工作组秘书长
中国抗癌协会血液肿瘤专业委员会青年委员
中国抗癌协会血液肿瘤委员会慢淋工作组委员
中国抗癌协会第一届T细胞淋巴瘤工作组委员
中国老年医学会血液学分会淋巴瘤学组委员
江苏省淋巴瘤联盟副主席
江苏省医学会血液学分会淋巴瘤/骨髓瘤学组委员
江苏省“六大人才高峰”培养对象
江苏省“科教强卫工程”青年医学人才
霍奇金淋巴瘤治疗现状和困境
霍奇金淋巴瘤（HL）在接受一线方案治疗后，10-15%的局限期患者和30-40%的晚期患者会面临复发[1, 2]。对于难治复发性经典型霍奇金淋巴瘤（r/r cHL）的治疗，传统的挽救性大剂量化疗（HDCT）桥接自体干细胞移植（ASCT）难以获得长期的生存获益，且HDCT和多线化疗带来的毒性较高，甚至存在发生二位肿瘤的远期风险，而不适合ASCT的患者，中位OS仅为1年[3, 4]。2021年欧洲血液学会（EHA）年会上公布的B-HOLISTIC研究中国亚组数据显示，初诊cHL和r/r cHL患者的5年PFS率分别为55.1%和29.8%。在该项国际多中心回顾性临床研究中，大多数东亚国家r/r cHL患者接受的治疗为HDCT序贯ASCT[5]。
图1. B-HOLISTIC研究中国亚组生存曲线
EBV病毒（EBV）驱动和9p24扩增介导的PD1/PDL1上调是cHL典型的病理特征，参与了免疫逃逸的发生[6]。PD1/PDL1抗体单药治疗r/r cHL可以获得17%-62.9%的CR率[7-9]。而靶向CD30的抗体欧联药物（ADC）维布妥昔单抗（BV）单药治疗r/r cHL，CR率可以达到24%-34%[10-12]。而基于BV，PD1/PDL1抗体以及其他联合治疗策略，则可以获得61%-95%的CR率[13-16]。
但是，即便在PD1/PDL1单抗和BV时代，仍然存在未被满足的临床需求，亟待寻求新的治疗办法[17-19]。嵌合抗原受体T（CAR-T）细胞治疗通过基因编辑，患者T淋巴细胞获得了精准靶向攻击肿瘤细胞的能力，CAR-T细胞治疗在B细胞血液肿瘤的治疗中，取得了较大成功，多款产品和适应症获批上市[20-23]。在真实世界中，年龄和体能不再是影响CAR-T细胞治疗的关键影响因素，适应症范围也在不断扩大[24-26]。寻求靶向cHL相关抗原的CAR-T细胞治疗有望成为PD1/PDL1单抗和BV时代之后的重要治疗选择。
图2. BV Ipi（b-I）、BV Nivo（b-N）和BV Nivo-Ipi（b-N-I）治疗组合的生存曲线；A：PFS; B：OS
CD30是CAR-T治疗的理想靶点
CD30是一种TNFR超家族细胞膜蛋白，是淋巴细胞活化相关的抗原，正常表达在活化的T/B细胞上，广泛表达于Reed-Sternberg（RS）细胞上，是cHL重要的诊断标记[27]。当CD30配体结合到CD30后，TRAF蛋白将介导CD30受体发出的信号，继而活化下游多个信号通路，调控细胞的增殖，凋亡等生物学行为[28]。
图3. CD30介导的下游信号通路
因此，CD30也是CAR-T细胞治疗的理想靶点[29]。截止目前，在Clinical Trial注册的在研靶向CD30 CAR-T细胞临床试验共23项，其中来自中国的注册临床试验9项。早在1998年发表的第一代靶向CD30的CAR-T研究，是可以追溯的较早针对cHL的CART细胞临床研究，证明了靶向CD30 CAR-T细胞治疗的可行性[30]。虽然造血干细胞以及活化T/B细胞也表达CD30分子，有潜在脱靶可能。但由于干细胞CD30抗原表达较弱，且干细胞具有独特的高表达SP6/P19分子，可以抵抗穿孔素颗粒酶的攻击和抗凋亡作用，靶向CD30-CAR-T细胞并不会造成干细胞损害以及T/B细胞的分化[31]。
图4. 抗CD30-CART不影响造血干细胞的集落分化/不影响T/B细胞分化
抗CD30 CAR-T治疗现状和优化策略
在过去的二十年中，靶向CD30 CAR-T细胞治疗r/r cHL的临床研究进展缓慢，总体获得的ORR可以达到30%-40%，且深度缓解较低，但具有较好的安全性，≥3级细胞因子释放综合征（CRS）基本在0%-5%，≥3级免疫效应细胞相关神经毒性综合征（ICANS）基本在0-2%[32]。为进一步提高靶向CD30 CAR-T的疗效，一些积极的措施逐渐被尝试。苯达莫司汀联合福达拉滨的清淋方案，有助于提高靶向CD30 CAR-T细胞治疗的早期应答，可以达到59%的CR率和72%的ORR[33]。共表达CCR4的CAR-T策略，有效促进CAR-T细胞的游走和归巢，增强杀瘤效应[34]。而通过联合CSF-1受体抑制剂可以有效解除MDSC的抑制，期待未来可以进入临床进行验证[35]。相比较于常规剂量（*10^6/kg）的CART治疗，高剂量（*10^7/kg）可以在靶向CD30 CAR-T细胞的治疗中获得更好的治疗应答[36]。周剑峰和张同存团队探索的第三代靶向CD30 CAR-T，有助于提高疗效[37, 38]。此外，由于20-40%的cHL为EBV驱动[39]，选择EBV-CTL作为工作细胞制备CAR-T，可以获得CAR-T和EBV-CTL叠加的杀伤效应[40]。此外，针对EBV阳性r/r cHL，靶向EBV编码抗原的CAR-T细胞治疗也是未来的发展方向[41]。基于记忆性T细胞来源的CAR-T细胞也具有更好的杀瘤效应[42]。
图5. 过表达CCR4有助于促进抗CD30-CART的“归巢”并增强CART的杀伤效应
靶向CD30 CAR-T的联合治疗策略
CAR-T细胞的联合治疗策略也是目前重要的临床实践和未来的探索方向。CAR-T细胞在体内激活之后，约30%细胞将会上调PD1分子，诱导CAR-T细胞耗竭，而通过PD1敲除或者联合可以有效促进CART的再激活和二次扩增[43, 44]。桑威教授和李彩霞教授团队在一项靶向CD30 CART细胞治疗的多中心临床研究中证明了高剂量（*10^7/kg）CAR-T细胞可以获得更好的疗效，此外，在联合了PD1抗体之后，可以达到80%的CR和100%的ORR[45]。在可评估的12例患者中，只有1例（8.3%）患者出现3级CRS，无任何级别ICANS发生。在该研究中，部分患者接受了在CAR-T细胞治疗后序贯HSCT和二次CAR-T的三明治疗策略，维持了较好的疗效，总体达到了70%的5年OS。黄亮教授团队寻求自体移植联合CD30 CART的策略治疗CD30阳性淋巴瘤也获得较好疗效[46]。
图6. PD1增强抗CD30 CART细胞治疗
图7. HSCT序贯抗CD30 CART治疗r/r cHL安全有效
靶向CD30 CAR-T治疗的未来展望
综上，靶向CD30 CAR-T是r/r cHL尤其是PD1/BV治疗失败患者重要的补充，且具有较高的安全性，年龄和体能也不再是CAR-T细胞治疗需要逾越的绝对障碍。由于cHL有效抗原载量较低，推荐高剂量的（*107/kg）给药剂量。而通过联合PD1/PDL1单抗以及HSCT，可以进一步提高抗CD30-CAR-T细胞治疗的疗效。对于EBV阳性cHL，可以考虑选择靶向EBV编码抗原，如靶向gp350的CAR-T细胞进行治疗。此外，尚未解决的问题包括CAR技术改进，可溶性PD1/CD30的影响，淋巴瘤微环境对CAR-T细胞治疗的影响，优化的预处理方案以及联合等增效策略需要进一步探索。
单位：徐州医科大学附属医院血液科淋巴瘤中心
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