荷兰癌症研究所Emile E. Voest和Myriam Chalabi小组研究有了新进展。他们发现新辅助免疫疗法可引起错配修复（MMR）完整（pMMR）和MMR缺乏（dMMR）的早期结肠癌病理反应。2020年4月6日，该成果发表在《自然-医学》杂志上。
研究人员假设在早期结肠癌中新辅助免疫疗法具有更高的疗效。在探索性NICHE研究中（ClinicalTrials.gov：NCT03026140），患有dMMR或pMMR肿瘤的患者在手术前接受单剂量的ipilimumab和两倍剂量的nivolumab治疗，并且pMMR患者使用或不使用塞来昔布。该试验的主要目的是安全性和可行性；参与治疗的40例肿瘤患者中有21人存在dMMR，20人存在 pMMR，其中3例在安全试用期内接受了nivolumab单药治疗。
所有患者均接受了无延迟的根治性切除并且治疗耐受良好，达到了主要目标。在接受ipilimumab + nivolumab治疗的患者（20 dMMR和15 pMMR肿瘤）中，有35例可评估疗效和实验目的。
在20/20（100％）dMMR肿瘤中观察到病理缓解，其中有19种主要病理缓解（MPR，≤10％残留存活肿瘤）和12种病理完全缓解。在pMMR肿瘤中，有4/15（27％）显示出病理缓解，其中3个MPR和1个部分缓解。 CD8 + PD-1 + T细胞浸润可预测pMMR肿瘤的应答。这些数据表明，新辅助免疫疗法可能在特定的结肠癌患者群体中成为标准治疗方法，并在具有至少3年无病生存数据的大型研究中得到验证。
据了解，PD-1加CTLA-4阻断对晚期MMR缺陷的大肠癌非常有效，但对pMMR的肿瘤无效。
附：英文原文
Title: Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers
Author: Myriam Chalabi, Lorenzo F. Fanchi, Krijn K. Dijkstra, Jos G. Van den Berg, Arend G. Aalbers, Karolina Sikorska, Marta Lopez-Yurda, Cecile Grootscholten, Geerard L. Beets, Petur Snaebjornsson, Monique Maas, Marjolijn Mertz, Vivien Veninga, Gergana Bounova, Annegien Broeks, Regina G. Beets-Tan, Thomas R. de Wijkerslooth, Anja U. van Lent, Hendrik A. Marsman, Elvira Nuijten, Niels F. Kok, Maria Kuiper, Wieke H. Verbeek, Marleen Kok, Monique E. Van Leerdam, Ton N. Schumacher, Emile E. Voest, John B. Haanen
Issue&Volume: 2020-04-06
Abstract: PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab+nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.
DOI: 10.1038/s41591-020-0805-8
Source: https://www.nature.com/articles/s41591-020-0805-8
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
本期文章：《自然—医学》：Online/在线发表
