Journal ArticleDOI
Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
Myriam Chalabi,Lorenzo F. Fanchi,Krijn K. Dijkstra,José G van den Berg,Arend G. J. Aalbers,Karolina Sikorska,Marta Lopez-Yurda,Cecile Grootscholten,Geerard L. Beets,Geerard L. Beets,Petur Snaebjornsson,Monique Maas,Marjolijn Mertz,Vivien Veninga,Gergana Bounova,Annegien Broeks,Regina G. H. Beets-Tan,Regina G. H. Beets-Tan,Thomas R de Wijkerslooth,Anja U. van Lent,Hendrik A Marsman,Elvira Nuijten,Niels F. M. Kok,Maria Kuiper,Wieke H M Verbeek,Marleen Kok,Monique E. van Leerdam,Ton N. Schumacher,Emile E. Voest,John B. A. G. Haanen +29 more
Reads0
Chats0
TLDR
The 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.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. Results from the NICHE study show remarkable pathological responses to neoadjuvant combination immunotherapy in patients with early-stage colon cancer and uncover potential biomarkers of response.read more
Citations
More filters
Journal ArticleDOI
High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types.
Daniel J. McGrail,Patrick G. Pilie,Naim U. Rashid,Leonie Voorwerk,Maarten Slagter,Marleen Kok,Eric Jonasch,Mustafa Khasraw,Amy B. Heimberger,Bora Lim,NT Ueno,Jennifer K. Litton,Renata Ferrarotto,Jeffrey T. Chang,S. L. Moulder,Sy Lin +15 more
TL;DR: In this article, the authors compared approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells, and found that TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors.
Journal ArticleDOI
The updated landscape of tumor microenvironment and drug repurposing.
Ming-Zhu Jin,Weilin Jin +1 more
TL;DR: An updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism micro environment, acidic niche, innervated niche, and mechanical microenvironment is presented and conventional drugs including aspirin, celecoxib, β-adrenergic antagonist, metformin, and statin are summarized in new antitumor application.
Journal ArticleDOI
PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer
TL;DR: In this article , a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma.
Journal ArticleDOI
The Next Decade of Immune Checkpoint Therapy.
Padmanee Sharma,Bilal A. Siddiqui,Swetha Anandhan,Shalini S. Yadav,Sumit K. Subudhi,Jianjun Gao,Sangeeta Goswami,James P. Allison +7 more
TL;DR: In this article, the authors survey the current understanding of mechanisms of response and resistance to ICT and propose a path forward to improving efficacy and minimizing toxicities through better patient selection and rational combinations.
Journal ArticleDOI
Tumor-infiltrating lymphocytes in the immunotherapy era.
TL;DR: While a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging, the search for response and prognostic biomarkers is just beginning.
References
More filters
Journal ArticleDOI
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
Journal ArticleDOI
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Paul C. Tumeh,Christina L. Harview,Jennifer H. Yearley,I. Peter Shintaku,Emma Taylor,Lidia Robert,Bartosz Chmielowski,Marko Spasic,Gina Henry,Voicu Ciobanu,Alisha N. West,Manuel Carmona,Christine Kivork,Elizabeth Seja,Grace Cherry,Antonio Gutierrez,Tristan Grogan,Christine Mateus,Gorana Tomasic,John A. Glaspy,Ryan O. Emerson,Harlan Robins,Robert H. Pierce,David Elashoff,Caroline Robert,Antoni Ribas +25 more
TL;DR: It is shown that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy.
Related Papers (5)
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer
Michael J. Overman,Sara Lonardi,Ka Yeung Mark Wong,Heinz-Josef Lenz,Fabio Gelsomino,Massimo Aglietta,Michael A. Morse,Eric Van Cutsem,Ray McDermott,Andrew Hill,Michael B. Sawyer,Alain Hendlisz,Bart Neyns,Magali Svrcek,Rebecca A. Moss,Jean Marie Ledeine,Z. Alexander Cao,Shital Kamble,Scott Kopetz,Thierry André +19 more
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
Dung T. Le,Dung T. Le,Jennifer N. Durham,Jennifer N. Durham,Kellie N. Smith,Hao Wang,Bjarne Bartlett,Bjarne Bartlett,Laveet K. Aulakh,Laveet K. Aulakh,Steve Lu,Steve Lu,Holly Kemberling,Cara Wilt,Brandon Luber,Fay Wong,Fay Wong,Nilofer S. Azad,Agnieszka A. Rucki,Daniel A. Laheru,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Tim F. Greten,Austin G. Duffy,Kristen K. Ciombor,Aleksandra Eyring,Bao H. Lam,Andrew K. Joe,S. Peter Kang,Matthias Holdhoff,Ludmila Danilova,Leslie Cope,Christian F. Meyer,Shibin Zhou,Shibin Zhou,Richard M. Goldberg,Deborah K. Armstrong,Katherine M. Bever,Amanda N. Fader,Janis M. Taube,Franck Housseau,David Spetzler,Nianqing Xiao,Drew M. Pardoll,Nickolas Papadopoulos,Nickolas Papadopoulos,Kenneth W. Kinzler,Kenneth W. Kinzler,James R. Eshleman,Bert Vogelstein,Bert Vogelstein,Robert A. Anders,Robert A. Anders,Luis A. Diaz,Luis A. Diaz +57 more
International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study
Franck Pagès,Bernhard Mlecnik,Florence Marliot,Gabriela Bindea,Gabriela Bindea,Gabriela Bindea,Fang Shu Ou,Carlo Bifulco,Alessandro Lugli,Inti Zlobec,Tilman T. Rau,Martin D. Berger,Iris D. Nagtegaal,Elisa Vink-Börger,Arndt Hartmann,Carol Geppert,Julie Kolwelter,Susanne Merkel,Robert Grützmann,Marc Van den Eynde,Anne Jouret-Mourin,Alex Kartheuser,Daniel Léonard,Christophe Remue,Julia Y. Wang,Julia Y. Wang,Prashant Bavi,Michael H.A. Roehrl,Michael H.A. Roehrl,Michael H.A. Roehrl,Pamela S. Ohashi,Linh T. Nguyen,Seong Jun Han,Heather L. MacGregor,Sara Hafezi-Bakhtiari,Bradly G. Wouters,Giuseppe Masucci,Emilia Andersson,Eva Zavadova,Michal Vocka,Jan Spacek,Lubos Petruzelka,Bohuslav Konopasek,Pavel Dundr,Helena Skalova,Kristyna Nemejcova,Gerardo Botti,Fabiana Tatangelo,Paolo Delrio,Gennaro Ciliberto,Michele Maio,Luigi Laghi,Fabio Grizzi,Tessa Fredriksen,Tessa Fredriksen,Tessa Fredriksen,Bénédicte Buttard,Bénédicte Buttard,Bénédicte Buttard,Mihaela Angelova,Mihaela Angelova,Mihaela Angelova,Angela Vasaturo,Angela Vasaturo,Angela Vasaturo,Pauline Maby,Pauline Maby,Pauline Maby,Sarah E. Church,Helen K. Angell,Lucie Lafontaine,Lucie Lafontaine,Lucie Lafontaine,Daniela Bruni,Daniela Bruni,Daniela Bruni,Carine El Sissy,Nacilla Haicheur,Amos Kirilovsky,Anne Berger,Christine Lagorce,Jeffrey P. Meyers,Christopher Paustian,Zipei Feng,Carmen Ballesteros-Merino,Jeroen R. Dijkstra,Carlijn van de Water,Shannon van Vliet,Nikki Knijn,Ana Maria Mușină,Dragos Viorel Scripcariu,Boryana Popivanova,Mingli Xu,Tomonobu Fujita,Shoichi Hazama,Nobuaki Suzuki,Hiroaki Nagano,Kiyotaka Okuno,Toshihiko Torigoe,Noriyuki Sato,Tomohisa Furuhata,Ichiro Takemasa,Kyogo Itoh,P. Patel,Hemangini H. Vora,Birva Shah,Jayendrakumar B. Patel,Kruti N. Rajvik,Shashank J. Pandya,Shilin N. Shukla,Yili Wang,Guanjun Zhang,Yutaka Kawakami,Francesco M. Marincola,Paolo A. Ascierto,Daniel J. Sargent,Bernard A. Fox,Bernard A. Fox,Jérôme Galon,Jérôme Galon,Jérôme Galon +120 more