联合免疫疗法可改善抗 PD1 单一疗法失败的复制修复缺陷 (RRD) 高级别神经胶质瘤的预后：国际 RRD 联盟的报告。
Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
发表日期：2023 Oct 12
作者：
Anirban Das, Nicholas R Fernandez, Adrian Levine, Vanessa Bianchi, Lucie K Stengs, Jiil Chung, Logine Negm, Jose Rafael Dimayacyac, Yuan Chang, Liana Nobre, Ayse B Ercan, Santiago Sanchez-Ramirez, Sumedha Sudhaman, Melissa Edwards, Valerie Larouche, David Samuel, An Van Damme, David Gass, David S Ziegler, Stefan S Bielack, Carl Koschmann, Shayna Zelcer, Michal Yalon-Oren, Gadi Abede Campino, Tomasz Sarosiek, Kim E Nichols, Rebecca Loret De Mola, Kevin Bielamowicz, Magnus Sabel, Charlotta A Frojd, Matthew D Wood, Jason M Glover, Yi-Yen Lee, Magimairajan Vanan, Jenny K Adamski, Sebastien Perreault, Omar Chamdine, Magnus Aasved Hjort, Michal Zapotocky, Fernando Carceller, Erin Wright, Ivana Fedorakova, Alexander Lossos, Ryuma Tanaka, Michael Osborn, Deborah T Blumenthal, Melyssa Aronson, Ute Bartels, Annie Huang, Vijay Ramaswamy, David Malkin, Adam Shlien, Anita Villani, Peter B Dirks, Trevor J Pugh, Gad Getz, Yosef E Maruvka, Derek S Tsang, Birgit Ertl-Wagner, Cynthia Hawkins, Eric Bouffet, Daniel A Morgenstern, Uri Tabori
来源：
Cancer Discovery
摘要：
免疫检查点抑制 (ICI) 对复制修复缺陷的高级别神经胶质瘤 (RRD-HGG) 有效。 ICI 单一疗法失败后免疫导向方法的临床/生物学影响尚不清楚。我们对 75 名接受抗 PD1 治疗的患者进行了一项国际研究； 20 例无进展（中位随访时间：3.7 年）。第二次进展/复发后 (n=55)，持续基于 ICI 的挽救将生存期延长至 11.6 个月 (n=38；p<0.001)，特别是对于那些突变负担极大的患者 (p=0.03)。观察到延迟的、持续的反应，与突变谱和免疫微环境的变化有关。对再辐射的反应是由于不存在有害的辐射后插入缺失特征（ID8）来解释的。随着时间的推移，CTLA4 表达增加，随后的 CTLA4 抑制导致 75% 的患者出现缓解/疾病稳定。 RAS-MAPK 通路抑制导致外周免疫和放射反应重新活跃。局部（突发）和全身免疫不良事件很常见（双等位基因错配修复缺陷>林奇综合征）。我们为 RRD-HGG 从免疫导向/协同挽救疗法中获得持续获益提供了机制原理。未来的方法需要根据患者和肿瘤生物学进行定制。
Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.