Domvanalimab

*仅供医学专业人士阅读参考如果要评选一个免疫治疗领域的“最惨靶点”，那奇点糕肯定会把票投给TIGIT：就在前两天，曾备受期待的TIGIT抑制剂Tiragolumab又挨了一闷棍，一线联合PD-L1抑制剂治疗肺癌的关键临床研究终究没达到阳性结果，恐怕在肺癌领域彻底翻身无望了。但同样是联合PD-L1抑制剂，TIGIT抑制剂治疗胃癌和食管癌的临床研究，近一年来可是喜报频传[1]。所以说，现在还真不能对TIGIT抑制剂的命运下定论，东方不亮西方亮也不是什么稀罕事，还是要更深入地了解TIGIT抑制剂的起效机制，帮它们找到适合的赛道和使用场景才行。近日，开发Tiragolumab的基因泰克（Genentech）公司团队就在Nature Cancer期刊发表最新研究成果[2]，揭示了TIGIT抑制剂与PD-L1抑制剂联合见效的最新作用机制证据。研究发现，同时抑制TIGIT与PD-L1可使肿瘤引流淋巴结（TDLNs）中的肿瘤反应性CD8+T细胞，在CD226的驱动下发生数量扩增并进入血液，随后肿瘤反应性CD8+T细胞浸润到肿瘤前，抑制TIGIT与PD-L1也会通过营造共刺激条件，使它们向效应表型而非耗竭表型分化，让进入肿瘤部位的CD8+T细胞更有利于发挥抗癌作用。论文首页截图基因泰克团队本次研究的切入点，是评估TIGIT抑制剂与PD-L1抑制剂是否会在T细胞激活的不同阶段或不同部位发挥作用，为此实验首先在小鼠模型上展开：联合使用TIGIT抑制剂与PD-L1抑制剂的抑癌效果明显优于二者分别单用，但联合治疗并未显著改变肿瘤或TDLNs的CD8+T细胞总数，而TDLNs当中的肿瘤反应性CD8+T细胞占比明显上升。与此同时，小鼠外周血内的肿瘤反应性CD8+T细胞也明显增多，但在联合治疗开始后早期使用免疫抑制剂盐酸芬戈莫德（FTY720），特异性阻断T细胞从TDLNs经血液循环的迁移，就会使TIGIT抑制剂与PD-L1抑制剂联合治疗的效果消失，意味着联合治疗必须依赖于肿瘤反应性CD8+T细胞经血液循环浸润到肿瘤部位这条路。TIGIT抑制剂与PD-L1抑制剂起效，依赖于肿瘤反应性CD8+T细胞经血液循环浸润到肿瘤研究者们根据表面标志物表达情况对肿瘤反应性CD8+T细胞进行了细分，发现在联合治疗后扩增的亚群以表达CD226为特征，且属于效应表型或耗竭表型，但联合治疗不会影响CD226表达阴性的肿瘤反应性CD8+T细胞；在肿瘤部位，受联合治疗影响的肿瘤反应性CD8+T细胞则会表达转录因子TCF1，意味着它们具有干细胞样特征，而换到TDLNs内，肿瘤反应性CD8+T细胞经联合治疗后的转录因子TOX表达减少，提示更不易走向耗竭。借助抗CD226单抗，研究者们又证实在TDLNs中，TIGIT抑制剂+PD-L1抑制剂对肿瘤反应性CD8+T细胞的调控确实依赖于CD226存在，TDLNs也是肿瘤反应性CD8+T细胞发生克隆扩增的主要部位；而且，肿瘤中浸润的CD8+T细胞也都经历过在TDLNs扩增这一步，后续浸润到肿瘤还会继续扩增，把肿瘤内“土生土长”的CD8+T细胞基本都挤走。对CD8+T细胞轨迹变化的分析则显示，TDLNs内具有干细胞样特征的一部分T细胞（特征为高表达Slamf6和Tcf7，类似记忆性干细胞样T细胞），是细胞毒性CD8+T细胞的主要来源；TIGIT抑制剂+PD-L1抑制剂的联合治疗，则会使肿瘤反应性CD8+T细胞更易发生迁移，且它们抵达肿瘤部位后更易分化为细胞毒性表型，杀伤癌细胞的能力更强，同时不易向肿瘤内原有CD8+T细胞的近似耗竭表型分化（PD-L1抑制剂+盐酸芬戈莫德处理可诱导）。TIGIT抑制剂+PD-L1抑制剂联合治疗对肿瘤反应性CD8+T细胞的整体影响总而言之，TIGIT抑制剂+PD-L1抑制剂联合治疗能够定向招募肿瘤反应性CD8+T细胞，并提升它们的整体质量，而不仅仅只有数量增多，这才是成功调动抗肿瘤免疫应答的关键。但从治疗消化道肿瘤的情况来看，好像TIGIT抑制剂+PD-L1抑制剂的双人成行还不够给力，总得加点化疗之类的元素才能真正成为“爆款”，看看未来科学家们还能挖出什么机制吧。参考文献：[1]Rha S Y, Oh D Y, Pelster M, et al. 130MO EDGE-Gastric Arm A1: Phase II study of domvanalimab (D), zimberelimab (Z), and FOLFOX in first-line (1L) advanced gastroesophageal (GE) cancer[J]. Annals of Oncology, 2024, 35(Supplement 4): S1455.[2]Nutsch K, Banta K L, Wu T D, et al. TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation[J]. Nature Cancer, 2024.本文作者丨谭硕

After multiple clinical failures, it’s finally the end of the road for Merck’s TIGIT program. The company is dropping development of its anti-TIGIT candidate vibostolimab after two more Phase 3 studies of a fixed-dose combination with Keytruda ended in disappointment. Merck is also discontinuing a separate LAG-3 targeting antibody asset called favezelimab, which it was also testing alongside Keytruda, according to a company release Tuesday. The pipeline cuts mean Merck won’t be able to stave off generic competition for its blockbuster PD-1 medicine by launching fixed-dose combinations with other targeted therapies, Leerink analysts wrote Tuesday. They added that the drugmaker will instead have to focus on converting patients to a subcutaneous formulation of Keytruda, which could launch as soon as next year. The decision to nix vibostolimab was made after two trials of the drug plus Keytruda in certain patients with non-small cell lung cancer — KeyVibe-003 and KeyVibe-007 — met prespecified futility criteria for the overall survival primary endpoint. These flops add to a spate of late-stage disappointments earlier this year in small cell lung cancer and skin cancer . The company is also axing the KeyVibe-006 test of vibostolimab plus Keytruda and chemoradiotherapy in stage 3 NSCLC, which is still enrolling, according to clinicaltrials.gov. Merck did not offer much explanation of what drove the most recent failures, but the Leerink analysts said TIGIT/PD-1 combinations tend to have high levels of toxicity that can lead to patients discontinuing treatment, making it difficult to establish a long-term survival benefit. Merck is not the only drugmaker that has struggled with developing TIGITs. Last month, Roche’s candidate tiragolumab plus its PD-L1 drug Tecentriq missed the OS primary endpoint in a registrational NSCLC test. But there’s still potential for TIGIT drugs that are Fc-incompetent because they could have better safety, the Leerink analysts said. These include Gilead and Arcus’ domvanalimab and Compugen’s COM902. Elsewhere, Merck stopped enrollment in the Phase 3 KEYFORM-008 trial of a fixed-dose combination of favezelimab and Keytruda in certain patients with relapsed or refractory classical Hodgkin lymphoma as it ended the broader KEYFORM development program. The company said the decision was not driven by safety concerns. In September, the favezelimab regimen failed a separate study in metastatic colorectal cancer.