黄慧强教授:淋巴瘤治疗进展显著,双特异性抗体等免疫治疗前景广阔

2019-09-02 佚名 ioncology

淋巴瘤是血液系统中最为常见的恶性肿瘤之一,其治疗先后经历了传统化疗及免疫化疗时代。目前,以免疫检查点抑制剂(PD-1单抗),双特异性抗体及CAR-T为代表的新型治疗手段在淋巴瘤领域中正显示出极其广阔的应用价值及前景。

淋巴瘤血液系统中最为常见的恶性肿瘤之一,其治疗先后经历了传统化疗及免疫化疗时代。目前,以免疫检查点抑制剂(PD-1单抗),双特异性抗体及CAR-T为代表的新型治疗手段在淋巴瘤领域中正显示出极其广阔的应用价值及前景。

原发性中枢神经系统淋巴瘤(PCNSL)治疗新进展

原发性中枢神经系统淋巴瘤(PCNSL)是一类较为罕见的结外侵袭性非霍奇金淋巴瘤(NHL)。目前,PCNSL的一线治疗主要以大剂量甲氨蝶呤(HD-MTX)为基础,并联合应用其他药物(例如替莫唑胺、大剂量阿糖胞苷、CD20单抗等),远期生存率大概50%左右。上述方案治疗后一旦出现复发,其预后则相当差,而颅脑放疗的疗效差且远期神经毒性大。

近年来,PCNSL在分子生物学领域也有一定的进展,研究发现原发性中枢神经系统弥漫大B细胞淋巴瘤通常为ABC亚型,多伴有MYD88突变,故应用BTK抑制剂治疗可获得不俗的疗效。此外,免疫检查点抑制剂PD-1单抗在PCNSL的治疗中有比较好的疗效,来那度胺可通过血脑屏障,也被证实在PCNSL治疗中有一定的作用。在国外,有相关研究将上述三种靶向药物(BTK抑制剂/PD-1单抗/来那度胺)联合应用于复发性PCNSL的治疗,值得注意的是,此种多药联合方案需特别警惕其毒副作用,以免产生严重的不良反应(AEs),因此多药联合目前仍处于临床试验阶段,其具体的组合方案及合适剂量有待于进一步临床探索。

双特异性抗体CD20/CD3在复发/难治B细胞淋巴瘤的治疗中的前景及价值

双特异性抗体如CD20/CD3在淋巴瘤,乃至于其他实体瘤领域中均有极其重要的前景及价值,它通过CD20靶向及结合肿瘤细胞,而CD3则靶向及结合T细胞,进而显着提高对肿瘤细胞的“免疫杀伤”作用。

国外已经上市了CD19/CD3双特异性抗体,并在B细胞肿瘤的治疗中显示出较好的疗效,但该药的半衰期非常短,故而应用次数多、价格极其昂贵。目前,国内外大型医药企业正在致力于全速开发新型的双特异性抗体的研究如CD20/CD3双特异性抗体Mosunetuzumab,CD20-TCB是一种新型“2:1”的T细胞接合双特异性抗体,经过基因工程学的改良后,其与肿瘤和免疫细胞结合的比例发生了改变,在保证产生有效肿瘤细胞杀伤作用的同时,也减轻了炎症因子释放的程度。当前,CD20/CD3双特异性抗体正处于积极的临床研究阶段,I期临床单药初步疗效,可以得到有效率55%,CR 27%,我们期待该药为复发/难治B细胞淋巴瘤带来更多的治疗获益。

PD-1单抗联合化疗在复发/难治霍奇金淋巴瘤中的进展

PD-1单抗在霍奇金淋巴瘤(HL)中的应用可谓率先开创了免疫治疗的新时代。研究显示,PD-1单抗(Nivolumab、Pembrolizumab或其他国内PD-1单抗)在复发/难治霍奇金淋巴瘤(R/R-HL)的治疗中显示出相当不俗的单药疗效,其总体有效率(ORR)可达60%~70%,完全缓解率(CR)可达20%~30%,并且缓解持续时间较为持久。

为了进一步提高R/R-HL的疗效,目前PD-1单抗联合其他药物成为研究的热点方向。例如,PD-1单抗联合地西他滨可显着改善PD-1单抗对R/R-HL患者的有效率(ORR)、完全缓解率(CR)及缓解持续时间(DOR),这是非常明显的协同作用,目前正在积极的研究探索中。此外,PD-1单抗联合化疗方案在R/R-HL的治疗中亦取得了一定的进展,例如PD-1单抗联合GVD、ICE方案等。值得注意的是,PD-1单抗联合CD30单抗或自体移植(ASCT)也显示出广阔的前景。总体言之,PD-1单抗在复发/难治霍奇金淋巴瘤领域中已经进入了联合治疗的探索阶段,疗效不断提升,但同时也需要警惕和密切随访其免疫治疗毒副作用。

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    2020-04-01 amyloid
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    2019-09-05 研发小兵

    双特异性抗体是热点,但是也不一定都有效!

    0

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