Skip to main content
Top

29-08-2017 | Gastrointestinal cancers | Article

Immunotherapy in Colorectal Cancer: Where Are We Now?

Journal: Current Colorectal Cancer Reports

Authors: Trevor R. Baybutt, Allison A. Aka, Adam E. Snook

Publisher: Springer US

Abstract

Purpose of Review

This review examines the current state of colorectal cancer (CRC) immunotherapy across multiple treatment modalities and discusses some of the most promising approaches.

Recent Findings

CRC immunotherapy involving viral vector and dendritic cell vaccines, checkpoint blockade, and adoptive cell therapy has been explored from preclinical to clinical studies. Despite successes in other malignancies, including melanoma, leukemia, lung, and renal cancers, immunotherapies have been FDA approved for only a small subset of CRCs. Recent studies leveraging greater understanding of cellular and molecular mechanisms underlying colorectal tumorigenesis and immunotherapeutic mechanism of action may be exploited in upcoming trials.

Summary

While immune infiltration of CRC has been an established indicator of patient outcomes, immunotherapeutic strategies to date have not exploited its potential immunogenicity to benefit patients. New vaccine, checkpoint inhibitor, and CAR-T cell therapy paradigms promise to change that. With continued research, we could see a rapid increase in the number of FDA-approved immunotherapies for CRC in the coming years.
Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. https://​doi.​org/​10.​3322/​caac.​21332.CrossRefPubMed
2.
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. https://​doi.​org/​10.​1056/​NEJMoa1200690.CrossRefPubMedPubMedCentral
3.
Lal N, Beggs AD, Willcox BE, Middleton GW. An immunogenomic stratification of colorectal cancer: implications for development of targeted immunotherapy. Oncoimmunology. 2015;4(3):e976052. https://​doi.​org/​10.​4161/​2162402X.​2014.​976052.CrossRefPubMedPubMedCentral
4.
Maby P, Tougeron D, Hamieh M, Mlecnik B, Kora H, Bindea G, et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res. 2015;75(17):3446–55. https://​doi.​org/​10.​1158/​0008-5472.​CAN-14-3051.CrossRefPubMed
5.
•• Ahn SM, Ansari AA, Kim J, Kim D, Chun SM, Kim J, et al. The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy. Oncotarget. 2016;7(42):68638–49. https://​doi.​org/​10.​18632/​oncotarget.​11862. Identifies a potential subset of MSS + CRC that could be responsive to PD-1 therapy CrossRefPubMedPubMedCentral
6.
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. https://​doi.​org/​10.​1126/​science.​1129139.CrossRefPubMed
7.
Galon J, Pages F, Marincola FM, Angell HK, Thurin M, Lugli A, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med. 2012;10:205. https://​doi.​org/​10.​1186/​1479-5876-10-205.CrossRefPubMedPubMedCentral
8.
• Farsaci B, Donahue RN, Grenga I, Lepone LM, Kim PS, Dempsey B, et al. Analyses of pretherapy peripheral immunoscore and response to vaccine therapy. Cancer Immunol Res. 2016;4(9):755–65. https://​doi.​org/​10.​1158/​2326-6066.​CIR-16-0037. Describes a peripheral immunoscore that may have utility in identifying patients who have successfull responded to immunotherapy CrossRefPubMedPubMedCentral
9.
Ju H, Xing W, Yang J, Zheng Y, Jia X, Zhang B, et al. An effective cytokine adjuvant vaccine induces autologous T-cell response against colon cancer in an animal model. BMC Immunol. 2016;17(1):31. https://​doi.​org/​10.​1186/​s12865-016-0172-x.CrossRefPubMedPubMedCentral
10.
Zheng L, Edil BH, Soares KC, El-Shami K, Uram JN, Judkins C, et al. A safety and feasibility study of an allogeneic colon cancer cell vaccine administered with a granulocyte-macrophage colony stimulating factor-producing bystander cell line in patients with metastatic colorectal cancer. Ann Surg Oncol. 2014;21(12):3931–7. https://​doi.​org/​10.​1245/​s10434-014-3844-x.CrossRefPubMedPubMedCentral
11.
Morse MA, Niedzwiecki D, Marshall JL, Garrett C, Chang DZ, Aklilu M, et al. A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Ann Surg. 2013;258(6):879–86. https://​doi.​org/​10.​1097/​SLA.​0b013e318292919e​.CrossRefPubMed
12.
Duggan MC, Jochems C, Donahue RN, Richards J, Karpa V, Foust E, et al. A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-alpha-2b in patients with CEA-expressing carcinomas. Cancer Immunol Immunother. 2016;65(11):1353–64. https://​doi.​org/​10.​1007/​s00262-016-1893-7.CrossRefPubMed
13.
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. https://​doi.​org/​10.​1038/​mt.​2015.​109.CrossRefPubMedPubMedCentral
14.
Kibe S, Yutani S, Motoyama S, Nomura T, Tanaka N, Kawahara A, et al. Phase II study of personalized peptide vaccination for previously treated advanced colorectal cancer. Cancer Immunol Res. 2014;2(12):1154–62. https://​doi.​org/​10.​1158/​2326-6066.​CIR-14-0035.CrossRefPubMed
15.
Jin C, Liu Y, Zhu J, Xia T, Zhang B, Fei Y, et al. Recombinant Salmonella-based CEACAM6 and 4-1BBL vaccine enhances T-cell immunity and inhibits the development of colorectal cancer in rats: in vivo effects of vaccine containing 4-1BBL and CEACAM6. Oncol Rep. 2015;33(6):2837–44. https://​doi.​org/​10.​3892/​or.​2015.​3901.CrossRefPubMed
16.
Snook A, Baybutt T, Mastrangelo M, Lewis N, Goldstein S, Kraft W et al. A phase I study of Ad5-GUCY2C-PADRE in stage I and II colon cancer patients. Journal for ImmunoTherapy of Cancer 2015;3(Suppl 2):P450. https://​doi.​org/​10.​1186/​2051-1426-3-s2-p450.
17.
Snook AE, Baybutt TR, Hyslop T, Waldman SA. Preclinical evaluation of a replication-deficient recombinant adenovirus serotype 5 vaccine expressing guanylate cyclase C and the PADRE T-helper epitope. Hum Gene Ther Methods. 2016;27(6):238–50. https://​doi.​org/​10.​1089/​hgtb.​2016.​114.CrossRefPubMed
18.
Snook AE, Magee MS, Schulz S, Waldman SA. Selective antigen-specific CD4(+) T-cell, but not CD8(+) T- or B-cell, tolerance corrupts cancer immunotherapy. Eur J Immunol. 2014;44(7):1956–66. https://​doi.​org/​10.​1002/​eji.​201444539.CrossRefPubMedPubMedCentral
19.
• Witek M, Blomain ES, Magee MS, Xiang B, Waldman SA, Snook AE. Tumor radiation therapy creates therapeutic vaccine responses to the colorectal cancer antigen GUCY2C. Int J Radiat Oncol Biol Phys. 2014;88(5):1188–95. https://​doi.​org/​10.​1016/​j.​ijrobp.​2013.​12.​043. Radiation as an adjuvant to vaccination is being examined in multiple other cancers and has been shown to work synergistically to promote tumor regression in mouse models. This paper suggests that combination immunotherapy should be strongly considered for patients with rectal cancer or metastatic CRC CrossRefPubMedPubMedCentral
20.
•• Le DT UJN, 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. https://​doi.​org/​10.​1056/​NEJMoa1500596. Confirms the hypothesis that MSI + but not MSS + CRC is responsive to PD-1 blockade CrossRef
21.
Dunne PD, McArt DG, O'Reilly PG, Coleman HG, Allen WL, Loughrey M, et al. Immune-derived PD-L1 gene expression defines a subgroup of stage II/III colorectal cancer patients with favorable prognosis who may be harmed by adjuvant chemotherapy. Cancer Immunol Res. 2016;4(7):582–91. https://​doi.​org/​10.​1158/​2326-6066.​CIR-15-0302.CrossRefPubMed
22.
Andre T, Lonardi S, Wong KYM, Morse M, McDermott RS, Hill AG, et al. Combination of nivolumab (nivo) + ipilimumab (ipi) in the treatment of patients (pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142 study. J Clin Oncol. 2017;35(15_suppl):3531. https://​doi.​org/​10.​1200/​JCO.​2017.​35.​15_​suppl.​3531.
23.
Bendell JC, Kim TW, Goh BC, Wallin J, Oh D-Y, Han S-W, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016;34(15_suppl):3502. https://​doi.​org/​10.​1200/​JCO.​2016.​34.​15_​suppl.​3502.
24.
Zhao H, Wang Y, Yu J, Wei F, Cao S, Zhang X, et al. Autologous cytokine-induced killer cells improves overall survival of metastatic colorectal cancer patients: results from a phase II clinical trial. Clin Colorectal Cancer. 2016;15(3):228–35. https://​doi.​org/​10.​1016/​j.​clcc.​2016.​02.​005.CrossRefPubMed
25.
Zhu Y, Zhang H, Li Y, Bai J, Liu L, Liu Y, et al. Efficacy of postoperative adjuvant transfusion of cytokine-induced killer cells combined with chemotherapy in patients with colorectal cancer. Cancer Immunol Immunother. 2013;62(10):1629–35. https://​doi.​org/​10.​1007/​s00262-013-1465-z.CrossRefPubMed
26.
Lin T, Song C, Chuo DY, Zhang H, Zhao J. Clinical effects of autologous dendritic cells combined with cytokine-induced killer cells followed by chemotherapy in treating patients with advanced colorectal cancer: a prospective study. Tumour Biol. 2016;37(4):4367–72. https://​doi.​org/​10.​1007/​s13277-015-3957-2.CrossRefPubMed
27.
Li X, Dai X, Shi L, Jiang Y, Chen X, Chen L, et al. Phase II/III study of radiofrequency ablation combined with cytokine-induced killer cells treating colorectal liver metastases. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2016;40(1–2):137–45. https://​doi.​org/​10.​1159/​000452531.CrossRef
28.
•• Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375(23):2255–62. https://​doi.​org/​10.​1056/​NEJMoa1609279. Presents proof-of-concept evidence that adoptively transferred, targeted T cell therapy can have lasting therapeutic efficacy in a patient with metastatic CRC CrossRefPubMedPubMedCentral
29.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. https://​doi.​org/​10.​1056/​NEJMoa1407222.CrossRefPubMedPubMedCentral
30.
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. https://​doi.​org/​10.​1056/​NEJMoa1215134.CrossRefPubMedPubMedCentral
31.
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. https://​doi.​org/​10.​1056/​NEJMoa1103849.CrossRefPubMedPubMedCentral
32.
Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. https://​doi.​org/​10.​1126/​scitranslmed.​3002842.CrossRefPubMedPubMedCentral
33.
Zhang T, Cao L, Xie J, Shi N, Zhang Z, Luo Z, et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget. 2015;6(32):33961–71. https://​doi.​org/​10.​18632/​oncotarget.​5582.CrossRefPubMedPubMedCentral
34.
Wang L, Ma N, Okamoto S, Amaishi Y, Sato E, Seo N, et al. Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome. Oncoimmunology. 2016;5(9):e1211218. https://​doi.​org/​10.​1080/​2162402X.​2016.​1211218.CrossRefPubMedPubMedCentral
35.
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. https://​doi.​org/​10.​1038/​mt.​2010.​272.CrossRefPubMed
36.
• 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. https://​doi.​org/​10.​1158/​1078-0432.​CCR-14-1421. Presents Phase I clinical data suggested that CEA-specific CAR-T cell therapy could be a safe and effective local therapy for hepatic CRC metastases following hepatic artery infusion CrossRefPubMedPubMedCentral
37.
•• Magee MS, Kraft CL, Abraham TS, Baybutt TR, Marszalowicz GP, Li P, et al. GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity. Oncoimmunology. 2016;5(10):e1227897. https://​doi.​org/​10.​1080/​2162402X.​2016.​1227897. Presents preclinical data supporting GUCY2C as a safe and effective target for CAR-T cell therapy against metastatic CRC CrossRefPubMedPubMedCentral
38.
Snook AE, Waldman SA. Advances in cancer immunotherapy. Discov Med. 2013;15(81):120–5.PubMedPubMedCentral
39.
Anassi E, Ndefo UA. Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. Pharmacy and Therapeutics. 2011;36(4):197–202.PubMedPubMedCentral
40.
Newick K, Moon E, Albelda SM. Chimeric antigen receptor T-cell therapy for solid tumors. Mol Ther Oncolytics. 2016;3:16006. https://​doi.​org/​10.​1038/​mto.​2016.​6.CrossRefPubMedPubMedCentral
41.
Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy Science. 2013;342(6165):1432–3. https://​doi.​org/​10.​1126/​science.​342.​6165.​1432.PubMed