Skip to main content

Advertisement

SpringerLink
Log in

The current status and prospect of immunotherapy in colorectal cancer

  • REVIEW ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669–85.

    CAS  PubMed  Google Scholar 

  2. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res. 2012;18(6):1506–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wrobel P, Ahmed S. Current status of immunotherapy in metastatic colorectal cancer. Int J Colorectal Dis, 2019;34(1):13–25.

  5. Battaglin F, Naseem M, Lenz HJ, Salem ME. Microsatellite instability in colorectal cancer: overview of its clinical significance and novel perspectives. Clin Adv Hematol Oncol. 2018;16(11):735–45.

    PubMed  PubMed Central  Google Scholar 

  6. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Asaoka Y, Ijichi H, Koike K. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015;373(20):1979.

  8. Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol, 2019;16(6):361-375.

  9. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813–20.

    CAS  PubMed  Google Scholar 

  11. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med, 2020;383(23):2207–2218.

  12. Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov, 2015;5(1):16-18.

  13. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492–504.

    CAS  PubMed  Google Scholar 

  14. Lorenzen S, Lordick F, Loosen SH, Tacke F, Trautwein C, Roderburg C, et al. Current status of immunotherapy in gastrointestinal malignancies. Z Gastroenterol, 2020;58(6):542–555.

  15. Johdi NA, Sukor NF. Colorectal cancer immunotherapy: options and strategies. Front Immunol. 2020;11:1624.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Le DT, Kim TW, Van Cutsem E, Geva R, Jager D, Hara H, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11–9.

    CAS  PubMed  Google Scholar 

  17. Zhang X, Wu T, Cai X, Dong J, Xia C, Zhou Y, et al. Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities. Front Immunol, 2022;13: 795972.

  18. O'Neil BH, Wallmark JM, Lorente D, Elez E, Raimbourg J, Gomez-Roca C, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS One, 2017;12(12): e0189848.

  19. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Morse MA, Overman MJ, Hartman L, Khoukaz T, Brutcher E, Lenz HJ, et al. Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Oncologist, 2019;24(11):1453–1461.

  21. 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.

    CAS  PubMed  Google Scholar 

  22. Kim JH, Kim SY, Baek JY, Cha YJ, Ahn JB, Kim HS, et al. A phase II study of avelumab monotherapy in patients with mismatch repair-deficient/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer. Cancer Res Treat. 2020;52(4):1135–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Casak SJ, Marcus L, Fashoyin-Aje L, Mushti SL, Cheng J, Shen YL, et al. FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. Clin Cancer Res, 2021;27(17):4680–4684.

  24. Diaz LA, Jr., Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol, 2022;23(5):659–670.

  25. Grothey A. Pembrolizumab in MSI-H-dMMR Advanced Colorectal Cancer - A New Standard of Care. N Engl J Med, 2020;383(23):2283–2285.

  26. Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(5):665–77.

    CAS  PubMed  Google Scholar 

  27. Andre T, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol. 2022;33(10):1052–60.

    CAS  PubMed  Google Scholar 

  28. Lenz HJ, Van Cutsem E, Luisa Limon M, Wong KYM, Hendlisz A, Aglietta M, et al. 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;40(2):161–70.

    CAS  PubMed  Google Scholar 

  29. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566–76.

    CAS  PubMed  Google Scholar 

  30. Hu H, Kang L, Zhang J, Wu Z, Wang H, Huang M, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7(1):38–48.

    PubMed  Google Scholar 

  31. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen G, Jin Y, Guan WL, Zhang RX, Xiao WW, Cai PQ, et al. Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study. Lancet Gastroenterol Hepatol. 2023;8(5):422–31.

    PubMed  Google Scholar 

  33. Ludford K, Ho WJ, Thomas JV, Raghav KPS, Murphy MB, Fleming ND, et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol. 2023;41(12):2181–90.

    CAS  PubMed  Google Scholar 

  34. Eng C, Kim TW, Bendell J, Argiles G, Tebbutt NC, Di Bartolomeo M, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20(6):849–61.

    CAS  PubMed  Google Scholar 

  35. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15(5):325–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473–86.

    CAS  PubMed  Google Scholar 

  37. Cousin S, Cantarel C, Guegan JP, Gomez-Roca C, Metges JP, Adenis A, et al. Regorafenib-avelumab combination in patients with microsatellite stable colorectal cancer (REGOMUNE): a single-arm, open-label. Phase II Trial Clin Cancer Res. 2021;27(8):2139–47.

    CAS  PubMed  Google Scholar 

  38. Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2020;38(18):2053–61.

    CAS  PubMed  Google Scholar 

  39. Wang F, He MM, Yao YC, Zhao X, Wang ZQ, Jin Y, et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/II clinical trial and gut microbiome analysis. Cell Rep Med. 2021;2(9): 100383.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018;7(3):746–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang F, Zhao Q, Wang YN, Jin Y, He MM, Liu ZX, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol. 2019;5(10):1504–6.

    PubMed  PubMed Central  Google Scholar 

  42. Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16(2):71–81.

    CAS  PubMed  Google Scholar 

  43. Wang C, Gong J, Tu TY, Lee PP, Fakih M. Immune profiling of microsatellite instability-high and polymerase epsilon (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy. J Gastrointest Oncol. 2018;9(3):404–15.

    PubMed  PubMed Central  Google Scholar 

  44. Rousseau B, Foote MB, Maron SB, Diplas BH, Lu S, Argiles G, et al. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N Engl J Med. 2021;384(12):1168–70.

    PubMed  PubMed Central  Google Scholar 

  45. Li SKH, Martin A. Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol Med. 2016;22(4):274–89.

    CAS  PubMed  Google Scholar 

  46. Kather JN, Halama N, Jaeger D. Genomics and emerging biomarkers for immunotherapy of colorectal cancer. Semin Cancer Biol, 2018;52(Pt 2):189–197.

  47. Masugi Y, Nishihara R, Yang J, Mima K, da Silva A, Shi Y, et al. Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut. 2017;66(8):1463–73.

    CAS  PubMed  Google Scholar 

  48. Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9(5):353–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Li J, Wu C, Hu H, Qin G, Wu X, Bai F, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer. Cancer Cell. 2023.

  50. Bao X, Wang D, Dai X, Liu C, Zhang H, Jin Y, et al. An immunometabolism subtyping system identifies S100A9(+) macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis. Cell Rep Med. 2023;4(4): 100987.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500–1.

    PubMed  PubMed Central  Google Scholar 

  52. Goodman AM, Sokol ES, Frampton GM, Lippman SM, Kurzrock R. Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy. Cancer Immunol Res, 2019, 7(10): 1570–1573.

  53. Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol, 2016;1(3):207–216.

  54. Chen YX, Wang ZX, Yuan SQ, Jiang TJ, Huang YS, Xu RH, et al. POLE/POLD1 mutation in non-exonuclease domain matters for predicting efficacy of immune-checkpoint-inhibitor therapy. Clin Transl Med. 2021;11(9): e524.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Jones JC, Renfro LA, Al-Shamsi HO, Schrock AB, Rankin A, Zhang BY, et al. (Non-V600) BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017;35(23):2624–30.

    PubMed  PubMed Central  Google Scholar 

  56. Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28(8):1713–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.

    Google Scholar 

  58. Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Bao Y, Zhai J, Chen H, Wong CC, Liang C, Ding Y, et al. Targeting m(6)A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer. Gut. 2023.

  60. Morano F, Raimondi A, Pagani F, Lonardi S, Salvatore L, Cremolini C, et al. Temozolomide followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite-stable, O(6)-methylguanine-DNA methyltransferase-silenced metastatic colorectal cancer: the MAYA trial. J Clin Oncol. 2022;40(14):1562–73.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yefei Shu & Song Zheng

  2. Department of Medical Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Song Zheng

  3. The Fourth Clinical School of Zhejiang Chinese Medical University, Hangzhou, China

    Song Zheng

Authors
  1. Yefei Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Song Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yefei Shu or Song Zheng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shu, Y., Zheng, S. The current status and prospect of immunotherapy in colorectal cancer. Clin Transl Oncol 26, 39–51 (2024). https://doi.org/10.1007/s12094-023-03235-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-023-03235-0

Keywords

Search

Navigation