CTLA-4 blockade in the treatment of colorectal cancer with microsatellite instability

Document Type: Review Article

Authors

Centro Hospitalar Universitário São João, Porto

Abstract

Context: Colorectal cancer is one of the most common tumours worldwide, with around 10-15% of these related to microsatellite instability which is, in turn, responsible for a high neoantigen load and subsequent high tumour mutational burden. These characteristics are responsible for the poor response of these tumours to chemotherapy, highlighting the need for a different approach in the treatment of patients with microsatellite unstable colorectal cancer. Immunotherapy was proven important in the treatment of these patients, with immune checkpoint inhibition such as CTLA-4 blockade being one of the most promising targets so far.
Evidence Acquisition: A PubMed search was done on February 2021 where the used query obtained a total of 33 articles. After the inclusion and exclusion criteria, a total of 21 articles were obtained and used in this narrative review.
Results: Several studies with microsatellite unstable colorectal tumours have been done in order to evaluate the advantages and adverse events of CTLA-4 blockade in these patients. Studies show a benefit regarding the progression-free survival, overall survival and overall response rates in patients receiving ipilimumab (anti-CTLA-4) when compared to those who weren’t. Besides, the main adverse events are manageable and are more tolerable than those observed with chemotherapy. Nonetheless, unlike PD-1 blockade, anti-CTLA-4 drugs are currently only approved for the use as a combination therapy in microsatellite unstable colorectal cancer, still awaiting approval as a monotherapy.
Conclusion: Microsatellite unstable colorectal tumours deserve a different treatment path, as their characteristics make these tumours poor responders to chemotherapy while at the same time great candidates for immunotherapy, namely with CTLA-4 inhibitors.

KEY-WORDS
Colorectal cancer; CTLA-4; Immune checkpoint; Immunotherapy; Ipilimumab; Microsatellite instability

Keywords


1.         Hirano, H., Takashima, A., Hamaguchi, T., Shida, D., Kanemitsu, Y., and Colorectal Cancer Study Group of the Japan Clinical Oncology, G., Current status and perspectives of immune checkpoint inhibitors for colorectal cancer. Jpn J Clin Oncol, 2021. 51(1): p. 10-19.
2.         Morse, M.A., Hochster, H., and Benson, A., Perspectives on Treatment of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitor Therapy. Oncologist, 2020. 25(1): p. 33-45.
3.         Afrasanie, V.A., Marinca, M.V., Alexa-Stratulat, T., Gafton, B., Paduraru, M., Adavidoaiei, A.M., Miron, L., and Rusu, C., KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer - practical implications for the clinician. Radiol Oncol, 2019. 53(3): p. 265-274.
4.         Russo, D.M.L.d.C. and Barbosa, L.E.R., PD-1 blockade as a future treatment for colorectal cancer with microsatellite instability. Journal of Coloproctology, 2021. 40(04): p. 412-420.
5.         Franke, A.J., Skelton, W.P., Starr, J.S., Parekh, H., Lee, J.J., Overman, M.J., Allegra, C., and George, T.J., Immunotherapy for Colorectal Cancer: A Review of Current and Novel Therapeutic Approaches. J Natl Cancer Inst, 2019. 111(11): p. 1131-1141.
6.         Nguyen, M., Tipping Smith, S., Lam, M., Liow, E., Davies, A., Prenen, H., and Segelov, E., An update on the use of immunotherapy in patients with colorectal cancer. Expert Rev Gastroenterol Hepatol, 2021. 15(3): p. 291-304.
7.         De Souza, A., Finding the hot spot: identifying immune sensitive gastrointestinal tumors. Transl Gastroenterol Hepatol, 2020. 5: p. 48.
8.         Thomas, J., Leal, A., and Overman, M.J., Clinical Development of Immunotherapy for Deficient Mismatch Repair Colorectal Cancer. Clin Colorectal Cancer, 2020. 19(2): p. 73-81.
9.         Loupakis, F., Maddalena, G., Depetris, I., Murgioni, S., Bergamo, F., Dei Tos, A.P., Rugge, M., Munari, G., Nguyen, A., Szeto, C., Zagonel, V., Lonardi, S., and Fassan, M., Treatment with checkpoint inhibitors in a metastatic colorectal cancer patient with molecular and immunohistochemical heterogeneity in MSI/dMMR status. J Immunother Cancer, 2019. 7(1): p. 297.
10.       Cohen, R., Pellat, A., Boussion, H., Svrcek, M., Lopez-Trabada, D., Trouilloud, I., Afchain, P., and Andre, T., Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency. Bull Cancer, 2019. 106(2): p. 137-142.
11.       Tan, E. and Sahin, I.H., Defining the current role of immune checkpoint inhibitors in the treatment of mismatch repair-deficient/microsatellite stability-high colorectal cancer and shedding light on future approaches. Expert Rev Gastroenterol Hepatol, 2021: p. 1-8.
12.       Wilt, C. and Le, D.T., Integrating Immunotherapy Into Colorectal Cancer Care. Oncology (Williston Park), 2018. 32(10): p. 494-8.
13.       Cohen, R., Bennouna, J., Meurisse, A., Tournigand, C., De La Fouchardiere, C., Tougeron, D., Borg, C., Mazard, T., Chibaudel, B., Garcia-Larnicol, M.L., Svrcek, M., Vernerey, D., Menu, Y., and Andre, T., RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study. J Immunother Cancer, 2020. 8(2).
14.       Chen, E.X., Jonker, D.J., Loree, J.M., Kennecke, H.F., Berry, S.R., Couture, F., Ahmad, C.E., Goffin, J.R., Kavan, P., Harb, M., Colwell, B., Samimi, S., Samson, B., Abbas, T., Aucoin, N., Aubin, F., Koski, S.L., Wei, A.C., Magoski, N.M., Tu, D., and O'Callaghan, C.J., Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA Oncol, 2020. 6(6): p. 831-838.
15.       Saad, P. and Kasi, A., Ipilimumab, in StatPearls. 2021: Treasure Island (FL).
16.       Das, S., Allen, A., and Berlin, J., Immunotherapy After Immunotherapy: Response Rescue in a Patient With Microsatellite Instability-high Colorectal Cancer Post-Pembrolizumab. Clin Colorectal Cancer, 2020. 19(2): p. 137-140.
17.       Rotte, A., Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res, 2019. 38(1): p. 255.
18.       Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. Cancer Discov, 2018. 8(3): p. 263.
19.       Overman, M.J., Lonardi, S., Wong, K.Y.M., Lenz, H.J., Gelsomino, F., Aglietta, M., Morse, M.A., Van Cutsem, E., McDermott, R., Hill, A., Sawyer, M.B., Hendlisz, A., Neyns, B., Svrcek, M., Moss, R.A., Ledeine, J.M., Cao, Z.A., Kamble, S., Kopetz, S., and Andre, T., Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol, 2018. 36(8): p. 773-779.
20.       Chu, J.N., Choi, J., Ostvar, S., Torchia, J.A., Reynolds, K.L., Tramontano, A., Gainor, J.F., Chung, D.C., Clark, J.W., and Hur, C., Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Cancer, 2019. 125(2): p. 278-289.
21.       Morse, M.A., Overman, M.J., Hartman, L., Khoukaz, T., Brutcher, E., Lenz, H.J., Atasoy, A., Shangguan, T., Zhao, H., and El-Rayes, B., Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Oncologist, 2019. 24(11): p. 1453-1461.
22.       Tauber, M., Cohen, R., Laly, P., Josselin, L., Andre, T., and Mekinian, A., Severe necrotizing myositis associated with long term anti-neoplastic efficacy following nivolumab plus ipilimumab combination therapy. Clin Rheumatol, 2019. 38(2): p. 601-602.