Abstract
Advancements in surgical technique, imaging, perioperative care, and systemic chemotherapy have improved survival for colorectal liver metastasis; however, long-term survival and curative therapies have remained largely elusive. Immunotherapy is a promising and innovative strategy in the treatment of multiple malignancies, and there is evidence to support its use in metastatic colorectal cancer. Emerging therapeutic approaches and data suggest that immunotherapy may be effective in improving outcomes for select patients with metastatic colorectal cancer to the liver.
Keywords
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Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271–89.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
House MG, Kemeny NE, Gonen M, Fong Y, Allen PJ, Paty PB, et al. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer. Ann Surg. 2011;254(6):851–6.
Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–80.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208–15.
Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005–16.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.
Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, et al. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer. 2004;91(9):1711–7.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.
Katz SC, Bamboat ZM, Maker AV, Shia J, Pillarisetty VG, Yopp AC, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20(3):946–55.
Maker AV, Ito H, Mo Q, Weisenberg E, Qin LX, Turcotte S, et al. Genetic evidence that intratumoral T-cell proliferation and activation are associated with recurrence and survival in patients with resected colorectal liver metastases. Cancer Immunol Res. 2015;3(4):380–8.
Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–4.
Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353(25):2654–66.
Prall F, Duhrkop T, Weirich V, Ostwald C, Lenz P, Nizze H, et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol. 2004;35(7):808–16.
Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10(9):909–15.
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.
Chung KY, Gore I, Fong L, Venook A, Beck SB, Dorazio P, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28(21):3485–90.
Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19(3):620–6.
Foon KA, John WJ, Chakraborty M, Sherratt A, Garrison J, Flett M, Bhattacharya-Chatterjee M. Clinical and immune responses in advanced colorectal cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. Clin Cancer Res. 1997;3(8):1267–76.
Wong JYC, Chu DZ, Yamauchi DM, Williams LE, Liu A, Wilczynski S, et al. A phase I radioimmunotherapy trial evaluating 90yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84.66 in patients with metastatic CEA-producing malignancies. Clin Cancer Res. 2000;6(10):3855–63.
Posner MC, Niedzwiecki D, Venook AP, Hollis DR, Kindler HL, Martin EW, et al. A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: cancer and leukemia group B study 89903. Ann Surg Oncol. 2008;15(1):158–64.
Mazzaferro V, Coppa J, Carrabba MG, Rivoltini L, Schiavo M, Regalia E, et al. Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res. 2003;9(9):3235–45.
Harrop R, Connolly N, Redchenko I, Valle J, Saunders M, Ryan MG, et al. Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res. 2006;12(11 Pt 1):3416–24.
Elkord E, Dangoor A, Drury NL, Harrop R, Burt DJ, Drijfhout JW, et al. An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing surgical resection of colorectal cancer liver metastases. J Immunother. 2008;31(9):820–9.
Harrop R, Drury N, Shingler W, Chikoti P, Redchenko I, Carroll MW, et al. Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses. Cancer Immunol Immunother. 2008;57(7):977–86.
Barth RJ Jr, Fisher DA, Wallace PK, Channon JY, Noelle RJ, Gui J, et al. A randomized trial of ex vivo CD40L activation of a dendritic cell vaccine in colorectal cancer patients: tumor-specific immune responses are associated with improved survival. Clin Cancer Res. 2010;16(22):5548–56.
Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res. 2015;21(14):3149–59.
Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. 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;18(9):1182–91.
Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–9.
Lou E, Marshall J, Aklilu M, Cole D, Chang D, Morse M. A phase II study of active immunotherapy with PANVAC or autologous, cultured dendritic cells infected with PANVAC after complete resection of hepatic metastases of colorectal carcinoma. Clin Colorectal Cancer. 2006;5(5):368–71.
Nagorsen D, Scheibenbogen C, Marincola FM, Letsch A, Keilholz U. Natural T cell immunity against cancer. Clin Cancer Res. 2003;9(12):4296–303.
Grenier JM, Yeung ST, Khanna KM. Combination immunotherapy: taking cancer vaccines to the next level. Front Immunol. 2018;9:610.
Klebanoff CA, Acquavella N, Yu Z, Restifo NP. Therapeutic cancer vaccines: are we there yet? Immunol Rev. 2011;239(1):27–44.
Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. 2014;11(9):509–24.
Naganuma H, Kono K, Mori Y, Takayoshi S, Stern PL, Tasaka K, et al. Oncofetal antigen 5T4 expression as a prognostic factor in patients with gastric cancer. Anticancer Res. 2002;22(2B):1033–8.
Starzynska T, Marsh PJ, Schofield PF, Roberts SA, Myers KA, Stern PL. Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma. Br J Cancer. 1994;69(5):899–902.
Starzynska T, Wiechowska-Kozlowska A, Marlicz K, Bromley M, Roberts SA, Lawniczak M, et al. 5T4 oncofetal antigen in gastric carcinoma and its clinical significance. Eur J Gastroenterol Hepatol. 1998;10(6):479–84.
Wrigley E, McGown AT, Rennison J, Swindell R, Crowther D, Starzynska T, et al. 5T4 oncofetal antigen expression in ovarian carcinoma. Int J Gynecol Cancer. 1995;5(4):269–74.
Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004;4(2):118–32.
Harris JE, Ryan L, Hoover HC Jr, Stuart RK, Oken MM, Benson AB 3rd, et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol. 2000;18(1):148–57.
Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S, et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet. 1999;353(9150):345–50.
Reid TR, Freeman S, Post L, McCormick F, Sze DY. Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin. Cancer Gene Ther. 2005;12(8):673–81.
Kemeny N, Brown K, Covey A, Kim T, Bhargava A, Brody L, et al. Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Hum Gene Ther. 2006;17(12):1214–24.
Geevarghese SK, Geller DA, de Haan HA, Horer M, Knoll AE, Mescheder A, et al. Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver. Hum Gene Ther. 2010;21(9):1119–28.
Breitbach CJ, Bell JC, Hwang TH, Kirn DH, Burke J. The emerging therapeutic potential of the oncolytic immunotherapeutic Pexa-Vec (JX-594). Oncolytic Virother. 2015;4:25–31.
Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19(3):329–36.
Park SH, Breitbach CJ, Lee J, Park JO, Lim HY, Kang WK, et al. Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer. Mol Ther. 2015;23(9):1532–40.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.
Hege KM, Bergsland EK, Fisher GA, Nemunaitis JJ, Warren RS, McArthur JG, et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J Immunother Cancer. 2017;5:22.
Zhang C, Wang Z, Yang Z, Wang M, Li S, Li Y, et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol Ther. 2017;25(5):1248–58.
Thorn M, Guha P, Cunetta M, Espat NJ, Miller G, Junghans RP, et al. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gene Ther. 2016;23(6):188–98.
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.
Bodmer W, Bishop T, Karran P. Genetic steps in colorectal cancer. Nat Genet. 1994;6(3):217–9.
Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61.
Abdel-Nabi HH, Schwartz AN, Higano CS, Wechter DG, Unger MW. Colorectal carcinoma: detection with indium-111 anticarcinoembryonic-antigen monoclonal antibody ZCE-025. Radiology. 1987;164(3):617–21.
Divgi CR, McDermott K, Griffin TW, Johnson DK, Schnobrich KE, Fallone PS, et al. Lesion-by-lesion comparison of computerized tomography and indium-111-labeled monoclonal antibody C110 radioimmunoscintigraphy in colorectal carcinoma: a multicenter trial. J Nucl Med. 1993;34(10):1656–61.
Lind P. Application of radioimmunodetection with a radiolabeled monoclonal antibody to CEA (BW 431/26) in colorectal and breast cancer. Pathol Biol (Paris). 1993;41(1):39.
Riva P, Moscatelli G, Paganelli G, Benini S, Siccardi A. Antibody-guided diagnosis: an Italian experience on CEA-expressing tumours. Int J Cancer Suppl. 1988;2:114–20.
Stillwagon GB, Order SE, Haulk T, Herpst J, Ettinger DS, Fishman EK, et al. Variable low dose rate irradiation (131I-anti-CEA) and integrated low dose chemotherapy in the treatment of nonresectable primary intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 1991;21(6):1601–5.
Duffy AG, Makarova-Rusher OV, Ulahannan SV, Rahma OE, Fioravanti S, Walker M, et al. Modulation of tumor eIF4E by antisense inhibition: a phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer. Int J Cancer. 2016;139(7):1648–57.
Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76(6):1367–80.
Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity. 1998;8(1):21–30.
Tamada K, Shimozaki K, Chapoval AI, Zhu G, Sica G, Flies D, et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat Med. 2000;6(3):283–9.
Yu P, Fu YX. Targeting tumors with LIGHT to generate metastasis-clearing immunity. Cytokine Growth Factor Rev. 2008;19(3–4):285–94.
Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y, et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol. 2004;5(2):141–9.
Yu P, Spiotto MT, Lee Y, Schreiber H, Fu YX. Complementary role of CD4+ T cells and secondary lymphoid tissues for cross-presentation of tumor antigen to CD8+ T cells. J Exp Med. 2003;197(8):985–95.
Mortarini R, Scarito A, Nonaka D, Zanon M, Bersani I, Montaldi E, et al. Constitutive expression and costimulatory function of LIGHT/TNFSF14 on human melanoma cells and melanoma-derived microvesicles. Cancer Res. 2005;65(8):3428–36.
Morel Y, Truneh A, Sweet RW, Olive D, Costello RT. The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol. 2001;167(5):2479–86.
Browning JL, Miatkowski K, Sizing I, Griffiths D, Zafari M, Benjamin CD, et al. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J Exp Med. 1996;183(3):867–78.
Zhai Y, Guo R, Hsu TL, Yu GL, Ni J, Kwon BS, et al. LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J Clin Invest. 1998;102(6):1142–51.
Qin JZ, Upadhyay V, Prabhakar B, Maker AV. Shedding LIGHT (TNFSF14) on the tumor microenvironment of colorectal cancer liver metastases. J Transl Med. 2013;11:70.
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Tran, T.B., Maker, A.V. (2020). Immunotherapy in the Management of Colorectal Cancer Liver Metastasis. In: Correia, M., Choti, M., Rocha, F., Wakabayashi, G. (eds) Colorectal Cancer Liver Metastases. Springer, Cham. https://doi.org/10.1007/978-3-030-25486-5_21
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