小柯机器人

加拿大多伦多病童医院Uri Tabori团队在研究中取得进展。他们发现生殖细胞DNA复制修复缺陷可作为儿童对PD-1抑制反应的基因组预测因子。这一研究成果发表在2022年1月6日出版的国际学术期刊《自然-医学》上。

尽管之前的研究表明免疫检查点抑制剂(ICI)并不适用于儿童，但研究人员假设由MMRD和PPD引起的超突变将改善这些患者在ICI治疗后的结果。使用国际联盟注册研究，研究人员对38名患者的45例进行性或复发性肿瘤进行了ICI治疗。在大多数患者中观察到持久的客观反应，最终的3年生存率为41.4%。高突变负荷可预测由MMRD+PPD造成超突变癌症的反应（>100突变/Mb）；而MS-indels预测具有较低突变负荷（10-100 突变/Mb）的MMRD肿瘤反应。

此外，即使在胶质瘤等“免疫学惰性”肿瘤中，这两种机制也与免疫浸润增加有关，从而产生了有利的反应。假性进展很常见，并且与肿瘤微环境和全身免疫激活有关。

此外，继续ICI治疗对复发性患者产生了持久的反应。该研究表明，先前未知对 ICI治疗有反应的肿瘤患者（包括中枢神经系统和同步性癌症）的生存率有所提高，并确定了突变负荷和MS-indel在预测对免疫治疗持续反应方面的双重作用。

研究人员表示，在由儿童生殖细胞DNA错配修复缺陷或聚合酶校对缺陷（MMRD 和 PPD）引发的癌症病人中会产生高频突变和微卫星插入-缺失（MS-indel）。由于对化学辐射的固有抵抗力，MMRD 和PPD癌症通常是致命的。

附：英文原文

Title: Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author: Das, Anirban, Sudhaman, Sumedha, Morgenstern, Daniel, Coblentz, Ailish, Chung, Jiil, Stone, Simone C., Alsafwani, Noor, Liu, Zhihui Amy, Karsaneh, Ola Abu Al, Soleimani, Shirin, Ladany, Hagay, Chen, David, Zatzman, Matthew, Cabric, Vanja, Nobre, Liana, Bianchi, Vanessa, Edwards, Melissa, Sambira Nahum, Lauren C,, Ercan, Ayse B., Nabbi, Arash, Constantini, Shlomi, Dvir, Rina, Yalon-Oren, Michal, Campino, Gadi Abebe, Caspi, Shani, Larouche, Valerie, Reddy, Alyssa, Osborn, Michael, Mason, Gary, Lindhorst, Scott, Bronsema, Annika, Magimairajan, Vanan, Opocher, Enrico, De Mola, Rebecca Loret, Sabel, Magnus, Frojd, Charlotta, Sumerauer, David, Samuel, David, Cole, Kristina, Chiaravalli, Stefano, Massimino, Maura, Tomboc, Patrick, Ziegler, David S., George, Ben, Van Damme, An, Hijiya, Nobuko, Gass, David, McGee, Rose B., Mordechai, Oz, Bowers, Daniel C., Laetsch, Theodore W., Lossos, Alexander, Blumenthal, Deborah T., Sarosiek, Tomasz, Yen, Lee Yi, Knipstein, Jeffrey, Bendel, Anne, Hoffman, Lindsey M., Luna-Fineman, Sandra, Zimmermann, Stefanie, Scheers, Isabelle, Nichols, Kim E., Zapotocky, Michal, Hansford, Jordan R., Maris, John M.

Issue&Volume: 2022-01-06

Abstract: Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100mutations per Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

DOI: 10.1038/s41591-021-01581-6

Source: https://www.nature.com/articles/s41591-021-01581-6

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex