METIMMOX-2: Metastatic pMMR/MSS Colorectal Cancer - Shaping Anti-Tumor Immunity by Oxaliplatin

Summary

Hypothesis: Patients with metastatic colorectal cancer with DNA mismatch repair-proficient (pMMR) function / microsatellite-stable (MSS) phenotype harbor a non-immunogenic disease that can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy, and may achieve durable disease control or even tumor eradication by the addition of immune checkpoint blockade therapy to the standard-of-care oxaliplatin-based treatment.

Timeline

Start

2022-10-05

Primary completion

2028-01-31

Completion

2028-03-01

Publications

• Background Abrahamsson H, Jensen BV, Berven LL, Nielsen DL, Saltyte Benth J, Johansen JS, Larsen FO, Johansen JS, Ree AH. Antitumour immunity invoked by hepatic arterial infusion of first-line oxaliplatin predicts durable colorectal cancer control after liver metastasis ablation: 8-12 years of follow-up. Int J Cancer. 2020 Apr 1;146(7):2019-2026. doi: 10.1002/ijc.32847. Epub 2020 Jan 7.
• Background Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699.
• Background Bains SJ, Abrahamsson H, Flatmark K, Dueland S, Hole KH, Seierstad T, Redalen KR, Meltzer S, Ree AH. Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer. Cancer Immunol Immunother. 2020 Mar;69(3):355-364. doi: 10.1007/s00262-019-02458-x. Epub 2019 Dec 31.
• Background Borcoman E, Kanjanapan Y, Champiat S, Kato S, Servois V, Kurzrock R, Goel S, Bedard P, Le Tourneau C. Novel patterns of response under immunotherapy. Ann Oncol. 2019 Mar 1;30(3):385-396. doi: 10.1093/annonc/mdz003.
• Background Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12.
• Background Dagenborg VJ, Marshall SE, Yaqub S, Grzyb K, Boye K, Lund-Iversen M, Hoye E, Berstad AE, Fretland AA, Edwin B, Ree AH, Flatmark K. Neoadjuvant chemotherapy is associated with a transient increase of intratumoral T-cell density in microsatellite stable colorectal liver metastases. Cancer Biol Ther. 2020 May 3;21(5):432-440. doi: 10.1080/15384047.2020.1721252. Epub 2020 Feb 26.
• Background Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.
• Background Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Martinez AB, Chan TA, Coukos G, Demaria S, Deutsch E, Draganov D, Edelson RL, Formenti SC, Fucikova J, Gabriele L, Gaipl US, Gameiro SR, Garg AD, Golden E, Han J, Harrington KJ, Hemminki A, Hodge JW, Hossain DMS, Illidge T, Karin M, Kaufman HL, Kepp O, Kroemer G, Lasarte JJ, Loi S, Lotze MT, Manic G, Merghoub T, Melcher AA, Mossman KL, Prosper F, Rekdal O, Rescigno M, Riganti C, Sistigu A, Smyth MJ, Spisek R, Stagg J, Strauss BE, Tang D, Tatsuno K, van Gool SW, Vandenabeele P, Yamazaki T, Zamarin D, Zitvogel L, Cesano A, Marincola FM. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer. 2020 Mar;8(1):e000337. doi: 10.1136/jitc-2019-000337.
• Background Grasso CS, Giannakis M, Wells DK, Hamada T, Mu XJ, Quist M, Nowak JA, Nishihara R, Qian ZR, Inamura K, Morikawa T, Nosho K, Abril-Rodriguez G, Connolly C, Escuin-Ordinas H, Geybels MS, Grady WM, Hsu L, Hu-Lieskovan S, Huyghe JR, Kim YJ, Krystofinski P, Leiserson MDM, Montoya DJ, Nadel BB, Pellegrini M, Pritchard CC, Puig-Saus C, Quist EH, Raphael BJ, Salipante SJ, Shin DS, Shinbrot E, Shirts B, Shukla S, Stanford JL, Sun W, Tsoi J, Upfill-Brown A, Wheeler DA, Wu CJ, Yu M, Zaidi SH, Zaretsky JM, Gabriel SB, Lander ES, Garraway LA, Hudson TJ, Fuchs CS, Ribas A, Ogino S, Peters U. Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov. 2018 Jun;8(6):730-749. doi: 10.1158/2159-8290.CD-17-1327. Epub 2018 Mar 6.
• Background Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, Bot BM, Morris JS, Simon IM, Gerster S, Fessler E, De Sousa E Melo F, Missiaglia E, Ramay H, Barras D, Homicsko K, Maru D, Manyam GC, Broom B, Boige V, Perez-Villamil B, Laderas T, Salazar R, Gray JW, Hanahan D, Tabernero J, Bernards R, Friend SH, Laurent-Puig P, Medema JP, Sadanandam A, Wessels L, Delorenzi M, Kopetz S, Vermeulen L, Tejpar S. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015 Nov;21(11):1350-6. doi: 10.1038/nm.3967. Epub 2015 Oct 12.
• Background Hadden WJ, de Reuver PR, Brown K, Mittal A, Samra JS, Hugh TJ. Resection of colorectal liver metastases and extra-hepatic disease: a systematic review and proportional meta-analysis of survival outcomes. HPB (Oxford). 2016 Mar;18(3):209-20. doi: 10.1016/j.hpb.2015.12.004. Epub 2016 Feb 1.
• Background Hoos A, Wolchok JD, Humphrey RW, Hodi FS. CCR 20th Anniversary Commentary: Immune-Related Response Criteria--Capturing Clinical Activity in Immuno-Oncology. Clin Cancer Res. 2015 Nov 15;21(22):4989-91. doi: 10.1158/1078-0432.CCR-14-3128.
• Background Kalanxhi E, Meltzer S, Schou JV, Larsen FO, Dueland S, Flatmark K, Jensen BV, Hole KH, Seierstad T, Redalen KR, Nielsen DL, Ree AH. Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer. Br J Cancer. 2018 May;118(10):1322-1328. doi: 10.1038/s41416-018-0085-y. Epub 2018 Apr 26.
• Background Lee JW, Stone ML, Porrett PM, Thomas SK, Komar CA, Li JH, Delman D, Graham K, Gladney WL, Hua X, Black TA, Chien AL, Majmundar KS, Thompson JC, Yee SS, O'Hara MH, Aggarwal C, Xin D, Shaked A, Gao M, Liu D, Borad MJ, Ramanathan RK, Carpenter EL, Ji A, de Beer MC, de Beer FC, Webb NR, Beatty GL. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature. 2019 Mar;567(7747):249-252. doi: 10.1038/s41586-019-1004-y. Epub 2019 Mar 6.
• Background Lenz HJ, Van Cutsem E, Luisa Limon M, Wong KYM, Hendlisz A, Aglietta M, Garcia-Alfonso P, Neyns B, Luppi G, Cardin DB, Dragovich T, Shah U, Abdullaev S, Gricar J, Ledeine JM, Overman MJ, Lonardi S. First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. J Clin Oncol. 2022 Jan 10;40(2):161-170. doi: 10.1200/JCO.21.01015. Epub 2021 Oct 12.
• Background Liao W, Overman MJ, Boutin AT, Shang X, Zhao D, Dey P, Li J, Wang G, Lan Z, Li J, Tang M, Jiang S, Ma X, Chen P, Katkhuda R, Korphaisarn K, Chakravarti D, Chang A, Spring DJ, Chang Q, Zhang J, Maru DM, Maeda DY, Zebala JA, Kopetz S, Wang YA, DePinho RA. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer. Cancer Cell. 2019 Apr 15;35(4):559-572.e7. doi: 10.1016/j.ccell.2019.02.008. Epub 2019 Mar 21.
• Background Meltzer S, Torgunrud A, Abrahamsson H, Solbakken AM, Flatmark K, Dueland S, Bakke KM, Bousquet PA, Negard A, Johansen C, Lyckander LG, Larsen FO, Schou JV, Redalen KR, Ree AH. The circulating soluble form of the CD40 costimulatory immune checkpoint receptor and liver metastasis risk in rectal cancer. Br J Cancer. 2021 Jul;125(2):240-246. doi: 10.1038/s41416-021-01377-y. Epub 2021 Apr 9.
• Background Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, Andre T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. doi: 10.1016/S1470-2045(17)30422-9. Epub 2017 Jul 19.
• Background Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, Lin YJ, Wojtkiewicz G, Iwamoto Y, Mino-Kenudson M, Huynh TG, Hynes RO, Freeman GJ, Kroemer G, Zitvogel L, Weissleder R, Pittet MJ. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity. 2016 Feb 16;44(2):343-54. doi: 10.1016/j.immuni.2015.11.024. Epub 2016 Feb 9.
• Background Rahma OE, Hodi FS. The Intersection between Tumor Angiogenesis and Immune Suppression. Clin Cancer Res. 2019 Sep 15;25(18):5449-5457. doi: 10.1158/1078-0432.CCR-18-1543. Epub 2019 Apr 3.
• Background Ree AH, Nygaard V, Russnes HG, Heinrich D, Nygaard V, Johansen C, Bergheim IR, Hovig E, Beiske K, Negard A, Borresen-Dale AL, Flatmark K, Maelandsmo GM. Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain. Cancer Immunol Res. 2019 May;7(5):701-706. doi: 10.1158/2326-6066.CIR-18-0777. Epub 2019 Feb 25.
• Background Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016 Mar;13(3):143-58. doi: 10.1038/nrclinonc.2015.209. Epub 2015 Nov 24.
• Background Stremitzer S, Vermeulen P, Graver S, Kockx M, Dirix L, Yang D, Zhang W, Stift J, Wrba F, Gruenberger T, Lenz HJ, Scherer SJ. Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases. Br J Cancer. 2020 May;122(10):1518-1524. doi: 10.1038/s41416-020-0812-z. Epub 2020 Mar 24.
• Background Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol. 2020 Jan;17(1):11-32. doi: 10.1038/s41571-019-0241-1. Epub 2019 Jul 9.
• Background Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, Aymeric L, Michaud M, Apetoh L, Barault L, Mendiboure J, Pignon JP, Jooste V, van Endert P, Ducreux M, Zitvogel L, Piard F, Kroemer G. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010 Jan 28;29(4):482-91. doi: 10.1038/onc.2009.356. Epub 2009 Nov 2.
• Background Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Kohne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Osterlund P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taieb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422. doi: 10.1093/annonc/mdw235. Epub 2016 Jul 5.
• Background Whiteside TL, Demaria S, Rodriguez-Ruiz ME, Zarour HM, Melero I. Emerging Opportunities and Challenges in Cancer Immunotherapy. Clin Cancer Res. 2016 Apr 15;22(8):1845-55. doi: 10.1158/1078-0432.CCR-16-0049.
• Background Zitvogel L, Kepp O, Senovilla L, Menger L, Chaput N, Kroemer G. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. Clin Cancer Res. 2010 Jun 15;16(12):3100-4. doi: 10.1158/1078-0432.CCR-09-2891. Epub 2010 Apr 26.
• Background Ostrup O, Dagenborg VJ, Rodland EA, Skarpeteig V, Silwal-Pandit L, Grzyb K, Berstad AE, Fretland AA, Maelandsmo GM, Borresen-Dale AL, Ree AH, Edwin B, Nygaard V, Flatmark K. Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget. 2017 Jul 18;8(44):76290-76304. doi: 10.18632/oncotarget.19350. eCollection 2017 Sep 29.

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