Rational design of anti-GITR-based combination immunotherapy
Rational design of anti-GITR-based combination immunotherapy
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DOI：
10.1038/s41591-019-0420-8
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发表时间：
2019-05-01
期刊：
影响因子：
82.9
通讯作者：
Merghoub, Taha
中科院分区：
文献类型：
--
作者：
Zappasodi, Roberta;Sirard, Cynthia;Merghoub, Taha
通过检查点阻断调节 T 细胞稳态机制可以有效促进内源性抗肿瘤 T 细胞反应(1-11)。然而，许多患者仍然没有从检查点封锁中受益(12)，这凸显了针对替代免疫途径的需要(13)。糖皮质激素诱导的肿瘤坏死因子受体相关蛋白 (GITR) 是免疫治疗的一个有吸引力的靶点，因为它能够促进效应 T 细胞 (T-eff) 功能 (14,15) 并阻碍调节性 T 细胞 (T-reg) 抑制 (16-20)。根据我们和其他人报道的激动剂抗 GITR 抗体的有效临床前抗肿瘤活性 (16,21,22)，我们启动了抗 GITR 抗体 TRX518 (NCT01239134) 的首次人体 1 期 GITR 激动试验。在这里，我们报告了 TRX518 单药治疗晚期癌症患者的安全性和免疫效果，并为未来临床试验中合理结合 GITR 激动和检查点阻断提供机制临床前证据。我们证明，TRX518 可将循环和肿瘤内 T-reg 细胞减少到类似程度，从而提供一种易于评估的抗 GITR 活性生物标志物。尽管 T-reg 减少且 T-eff:T-reg 比率增加，但尚未观察到实质性的临床反应。同样，在患有晚期肿瘤的小鼠中，由于持续衰竭，GITR 激动不足以激活溶细胞 T 细胞。我们证明，通过 PD-1 阻断来重振 T 细胞可以克服晚期肿瘤对抗 GITR 单一疗法的耐药性。这些发现促使我们开始研究 TRX518 对晚期难治性肿瘤患者的 PD-1 通路阻断作用 (NCT02628574)。
Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses(1-11). However, many patients still do not benefit from checkpoint blockade(12), highlighting the need for targeting of alternative immune pathways(13). Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (T-eff) functions(14,15) and hamper regulatory T cell (T-reg) suppression(16-20). On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others(16,21,22), we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 (NCT01239134). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral T-reg cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite T-reg reductions and increased T-eff: T-reg ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors (NCT02628574).