@article{9560135b183c477a8dcd5d0c2d0688b1,
title = "Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers",
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,",
keywords = "DNA MISMATCH REPAIR, COLORECTAL-CANCER, PD-1 BLOCKADE, GENERATION, TUMORS, NIVOLUMAB, SURVIVAL, THERAPY, EVASION, CELLS",
author = "Myriam Chalabi and Fanchi, {Lorenzo F.} and Dijkstra, {Krijn K.} and {van den Berg}, {Jose G.} and Aalbers, {Arend G.} and Karolina Sikorska and Marta Lopez-Yurda and Cecile Grootscholten and Beets, {Geerard L.} and Petur Snaebjornsson and Monique Maas and Marjolijn Mertz and Vivien Veninga and Gergana Bounova and Annegien Broeks and Beets-Tan, {Regina G.} and {de Wijkerslooth}, {Thomas R.} and {van Lent}, {Anja U.} and Marsman, {Hendrik A.} and Elvira Nuijten and Kok, {Niels F.} and Maria Kuiper and Verbeek, {Wieke H.} and Marleen Kok and {Van Leerdam}, {Monique E.} and Schumacher, {Ton N.} and Voest, {Emile E.} and Haanen, {John B.}",
note = "Funding Information: We thank all patients and their families for participating in the present study. We thank: the Core Facility of Molecular Pathology and Biobanking, L. Braaf, S. Cornelissen and D. Peters for their support in processing of samples; C. Van Rooijen for setting up CD8/ PD1 costains; R. Kerkhoven and the Genomics Core Facility for their support with sequencing; the Flow Cytometry Core Facility for their support in flow cytometry; J. Lips from Adaptive Biotechnologies for his support; L. Alvan Wijck from the scientific administration department for data management; L. Hoes, F. Weeber, J. Westra, S. Visser and S. Kaing for facilitating sample acquisition and processing; A. Van der Leun for support in TIL isolation; T. Korse, M. Lucas and E. Platte for PBMC acquisition and processing; A. Atsma, P. Bottenberg, S. Oosterloo, M. van Wijngaarden, P. Den Hartog and S. Dokter for patient care; M. Mok, I. Honing, M. Van Nes and N. De Jong for patient care in the OLVG; P. Drillenburg for sample acquisition; Merus for provision of antiPD1 for in vitro experiments; M. Toebes, X. Kong and M. Ligtenberg for the lentiviral HLAA2 vector and MART1 peptide; S. Vanhoutvin for legal support; A. Evans, D. Tauriello, G. Sonke and H. Van Tinteren for scientific input. The present study was funded by the BMS International ImmunoOncology Network and sponsored by the NKI. The funding source had no role in design and execution of the study, data analysis or writing of the manuscript. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = apr,
doi = "10.1038/s41591-020-0805-8",
language = "English",
volume = "26",
pages = "566--576",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}