351
Views
6
CrossRef citations to date
0
Altmetric
REVIEW

Immune Checkpoint Inhibitor-Based Combination Therapy for Colorectal Cancer: An Overview

&
Pages 1527-1540 | Received 12 Feb 2023, Accepted 19 Apr 2023, Published online: 26 Apr 2023

References

  • Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. doi:10.3322/caac.21708
  • Hoxha M, Zappacosta B. A review on the role of fatty acids in colorectal cancer progression. Front Pharmacol. 2022;13:1032806. doi:10.3389/fphar.2022.1032806
  • Peng X, Zhao G, Lin J, Li C. Interaction of mannose binding lectin and other pattern recognition receptors in human corneal epithelial cells during Aspergillus fumigatus infection. Int Immunopharmacol. 2018;63:161–169. doi:10.1016/j.intimp.2018.08.003
  • Zhang Q, Tang L, Zhou Y, He W, Li W. Immune checkpoint inhibitor-associated pneumonitis in non-small cell lung cancer: current understanding in characteristics, diagnosis, and management. Front Immunol. 2021;12:663986. doi:10.3389/fimmu.2021.663986
  • Lentz RW, Colton MD, Mitra SS, Messersmith WA. Innate immune checkpoint inhibitors: the next breakthrough in medical oncology? Mol Cancer Ther. 2021;20(6):961–974. doi:10.1158/1535-7163.MCT-21-0041
  • Dai W, Xu L, Yu X, et al. OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism. J Hepatol. 2020;72(5):909–923. doi:10.1016/j.jhep.2019.12.015
  • Ghidini M, Fusco N, Salati M, et al. The emergence of immune-checkpoint inhibitors in colorectal cancer therapy. Curr Drug Targets. 2021;22(9):1021–1033. doi:10.2174/1389450122666210204204415
  • Ding S, Han L. Newborn screening for genetic disorders: current status and prospects for the future. Pediatr Investig. 2022;6(4):291–298. doi:10.1002/ped4.12343
  • Zheng Y, Li Y, Feng J, et al. Cellular based immunotherapy for primary liver cancer. J Exp Clin Cancer Res. 2021;40(1):250. doi:10.1186/s13046-021-02030-5
  • Xu YP, Zhou YQ, Zhao YJ, et al. High level of CD73 predicts poor prognosis of intrahepatic cholangiocarcinoma. J Cancer. 2021;12(15):4655–4660. doi:10.7150/jca.51038
  • Amodio V, Lamba S, Chila R, et al. Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance. Cancer Cell. 2022;41:196–209.e5. doi:10.1016/j.ccell.2022.12.003
  • Caglayan M, Wilson SH. Pol mu dGTP mismatch insertion opposite T coupled with ligation reveals promutagenic DNA repair intermediate. Nat Commun. 2018;9(1):4213. doi:10.1038/s41467-018-06700-5
  • Baretti M, Le DT. DNA mismatch repair in cancer. Pharmacol Ther. 2018;189:45–62. doi:10.1016/j.pharmthera.2018.04.004
  • Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7(5):335–346. doi:10.1038/nrm1907
  • Olave MC, Graham RP. Mismatch repair deficiency: the what, how and why it is important. Genes Chromosomes Cancer. 2022;61(6):314–321. doi:10.1002/gcc.23015
  • Gemelli M, Cortinovis DL, Baggi A, et al. Immune checkpoint inhibitors in malignant pleural mesothelioma: a systematic review and meta-analysis. Cancers. 2022;14(24):6063. doi:10.3390/cancers14246063
  • Ren B, Shen J, Qian Y, Zhou T. Sarcopenia as a determinant of the efficacy of immune checkpoint inhibitors in non-small cell lung cancer: a meta-analysis. Nutr Cancer. 2022;1–11. doi:10.1080/01635581.2022.2153879
  • Jacoberger-Foissac C, Allard B, Allard D, Stagg J. Assessing the efficacy of immune checkpoint inhibitors in preclinical tumor models. Methods Mol Biol. 2023;2614:151–169. doi:10.1007/978-1-0716-2914-7_11
  • Waissengrin B, Leshem Y, Taya M, et al. The use of medical cannabis concomitantly with immune checkpoint inhibitors in non-small cell lung cancer: a sigh of relief? Eur J Cancer. 2022;180:52–61. doi:10.1016/j.ejca.2022.11.022
  • Roccuzzo G, Giordano S, Fava P, et al. Immune check point inhibitors in primary cutaneous T-cell lymphomas: biologic rationale, clinical results and future perspectives. Front Oncol. 2021;11:733770. doi:10.3389/fonc.2021.733770
  • Hernaez R, Avila MA. Immunogenomic classification of hepatocellular carcinoma patients for immune check-point inhibitors therapy: cui bono? Gut. 2022. doi:10.1136/gutjnl-2022-327132
  • Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–3895. doi:10.1002/j.1460-2075.1992.tb05481.x
  • Makaremi S, Asadzadeh Z, Hemmat N, et al. Immune checkpoint inhibitors in colorectal cancer: challenges and future prospects. Biomedicines. 2021;9(9):1075. doi:10.3390/biomedicines9091075
  • Gessani S, Belardelli F. Immune dysfunctions and immunotherapy in colorectal cancer: the role of dendritic cells. Cancers. 2019;11(10):1491. doi:10.3390/cancers11101491
  • Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413. doi:10.1126/science.aan6733
  • Diaz LA Jr, Le DT. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;373(20):1979. doi:10.1056/NEJMc1510353
  • Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036–1041. doi:10.1093/annonc/mdx029
  • O’Neil BH, Wallmark JM, Lorente D, 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. doi:10.1371/journal.pone.0189848
  • Le DT, Kim TW, Van Cutsem E, 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):11–19. doi:10.1200/JCO.19.02107
  • Benson AB, Venook AP, Al-Hawary MM, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(3):329–359. doi:10.6004/jnccn.2021.0012
  • Andre T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–2218. doi:10.1056/NEJMoa2017699
  • Overman MJ, McDermott R, Leach JL, 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):1182–1191. doi:10.1016/S1470-2045(17)30422-9
  • Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial. JAMA Oncol. 2020;6(11):1766–1772. doi:10.1001/jamaoncol.2020.4515
  • Andre TBD, Curigliano G, Curigliano G. Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: results from GARNET study. J Clin Oncol. 2021;39(suppl3):9. doi:10.1200/JCO.2021.39.3_suppl.9
  • Bhamidipati D, Raghav KPS, Morris VK, et al. Prognostic role of systemic inflammatory markers in patients with metastatic MSI-h/dMMR colorectal cancer receiving immunotherapy. J Clin Oncol. 2022;40(16_suppl):3524. doi:10.1200/JCO.2022.40.16_suppl.3524
  • Golstein P. Cytolytic T-cell melodrama. Nature. 1987;327(6117):12. doi:10.1038/327012a0
  • Mak TW. Gaining insights into the ontogeny and activation of T cells through the use of gene-targeted mutant mice. J Inflamm. 1995;45(2):79–84.
  • Sobhani N, Tardiel-Cyril DR, Davtyan A, Generali D, Roudi R, Li Y. CTLA-4 in regulatory T cells for cancer immunotherapy. Cancers. 2021;13(6):1440. doi:10.3390/cancers13061440
  • Michelson DA, Benoist C, Mathis D. CTLA-4 on thymic epithelial cells complements Aire for T cell central tolerance. Proc Natl Acad Sci U S A. 2022;119(48):e2215474119. doi:10.1073/pnas.2215474119
  • Janman D, Hinze C, Kennedy A, et al. Regulation of CTLA-4 recycling by LRBA and Rab11. Immunology. 2021;164(1):106–119. doi:10.1111/imm.13343
  • Horzum U, Yanik H, Taskiran EZ, Esendagli G. Effector Th1 cells under PD-1 and CTLA-4 checkpoint blockade abrogate the upregulation of multiple inhibitory receptors and by-pass exhaustion. Immunology. 2022;167(4):640–650. doi:10.1111/imm.13560
  • Fox TA, Houghton BC, Petersone L, et al. Therapeutic gene editing of T cells to correct CTLA-4 insufficiency. Sci Transl Med. 2022;14(668):eabn5811. doi:10.1126/scitranslmed.abn5811
  • Berezhnoy A, Sumrow BJ, Stahl K, et al. Development and preliminary clinical activity of PD-1-guided CTLA-4 blocking bispecific DART molecule. Cell Rep Med. 2020;1(9):100163. doi:10.1016/j.xcrm.2020.100163
  • Andrews LP, Yano H, Vignali DAA. Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups. Nat Immunol. 2019;20(11):1425–1434. doi:10.1038/s41590-019-0512-0
  • Abunasser AAA, Xue J, Balawi EJA, Zhu Y. Combination of the EP and anti-PD-1 pathway or anti-CTLA-4 for the phase III trial of small-cell lung cancer: a meta-analysis. J Oncol. 2021;2021:6662344. doi:10.1155/2021/6662344
  • Bredin P, Naidoo J. The gut microbiome, immune check point inhibition and immune-related adverse events in non-small cell lung cancer. Cancer Metastasis Rev. 2022;41(2):347–366. doi:10.1007/s10555-022-10039-1
  • Zhang R, Peng X, Lin J, et al. The role of SREC-I in innate immunity to aspergillus fumigatus keratitis. Invest Ophthalmol Vis Sci. 2021;62(9):12. doi:10.1167/iovs.62.9.12
  • Peng XD, Zhao GQ, Lin J, et al. Fungus induces the release of IL-8 in human corneal epithelial cells, via Dectin-1-mediated protein kinase C pathways. Int J Ophthalmol. 2015;8(3):441–447. doi:10.3980/j.issn.2222-3959.2015.03.02
  • Garralda E, Sukari A, Lakhani NJ, et al. A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. J Clin Oncol. 2021;39(15_suppl):3584. doi:10.1200/JCO.2021.39.15_suppl.3584
  • Huang S, Zhao Y, Liao P, et al. Different expression patterns of Vista concurrent with PD-1, Tim-3, and TIGIT on T cell subsets in peripheral blood and bone marrow from patients with multiple myeloma. Front Oncol. 2022;12:1014904. doi:10.3389/fonc.2022.1014904
  • Chen Y, Zhang Y, Wang B, et al. Blood clot scaffold loaded with liposome vaccine and siRNAs targeting PD-L1 and TIM-3 for effective DC activation and cancer immunotherapy. ACS Nano. 2022. doi:10.1021/acsnano.2c10797
  • Brauneck F, Fischer B, Witt M, et al. TIGIT blockade repolarizes AML-associated TIGIT(+) M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis. J Immunother Cancer. 2022;10(12). doi:10.1136/jitc-2022-004794
  • Wiede F, Lu KH, Du X, et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell antitumor immunity. Cancer Discov. 2022;12(3):752–773. doi:10.1158/2159-8290.CD-21-0694
  • Geuijen C, Tacken P, Wang LC, et al. A human CD137xPD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat Commun. 2021;12(1):4445. doi:10.1038/s41467-021-24767-5
  • Keck JG, He W, Buetow BS, et al. Validation of a clinically relevant humanized mouse model for the safety assessment of 4-1BB agonists utomilumab and urelumab. J Clin Oncol. 2022;40(16_suppl):e14602–e14602. doi:10.1200/JCO.2022.40.16_suppl.e14602
  • Crupi MJF, Taha Z, Janssen TJA, et al. Oncolytic virus driven T-cell-based combination immunotherapy platform for colorectal cancer. Front Immunol. 2022;13:1029269. doi:10.3389/fimmu.2022.1029269
  • Abedi Kiasari B, Abbasi A, Ghasemi Darestani N, et al. Combination therapy with nivolumab (anti-PD-1 monoclonal antibody): a new era in tumor immunotherapy. Int Immunopharmacol. 2022;113(PtA):109365. doi:10.1016/j.intimp.2022.109365
  • Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299–308. doi:10.1016/S1470-2045(15)00544-6
  • Lenz HJ, Van Cutsem E, Luisa Limon 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):161–170. doi:10.1200/JCO.21.01015
  • Abdullaev S, André T, Lei M, et al. A phase III study of nivolumab (NIVO), NIVO + ipilimumab (IPI), or chemotherapy (CT) for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): checkmate 8HW. J Clin Oncol. 2020;38(4_suppl):TPS266–TPS266. doi:10.1200/JCO.2020.38.4_suppl.TPS266
  • Sinicrope FA, Ou F-S, Zemla T, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502). J Clin Oncol. 2019;37(15_suppl):e15169–e15169. doi:10.1200/JCO.2019.37.15_suppl.e15169
  • Lau D, Cunningham D, Gillbanks A, et al. POLEM: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III dMMR or POLE exonuclease domain mutant colon cancer—A phase III randomized study. J Clin Oncol. 2019;37(15_suppl):TPS3615–TPS3615. doi:10.1200/JCO.2019.37.15_suppl.TPS3615
  • Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566–576. doi:10.1038/s41591-020-0805-8
  • Yuki S, Bando H, Tsukada Y, et al. Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. J Clin Oncol. 2020;38(15_suppl):4100. doi:10.1200/JCO.2020.38.15_suppl.4100
  • Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363–2376. doi:10.1056/NEJMoa2201445
  • Verschoor YL, Berg JVD, Beets G, et al. Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: final clinical analysis of the NICHE study. J Clin Oncol. 2022;40(16_suppl):3511. doi:10.1200/JCO.2022.40.16_suppl.3511
  • Chen L, Jiang X, Li Y, et al. How to overcome tumor resistance to anti-PD-1/PD-L1 therapy by immunotherapy modifying the tumor microenvironment in MSS CRC. Clin Immunol. 2022;237:108962. doi:10.1016/j.clim.2022.108962
  • Moretto R, Elliott A, Zhang J, et al. Homologous recombination deficiency alterations in colorectal cancer: clinical, molecular, and prognostic implications. J Natl Cancer Inst. 2022;114(2):271–279. doi:10.1093/jnci/djab169
  • Wang D, Zhang H, Xiang T, Wang G. Clinical application of adaptive immune therapy in MSS colorectal cancer patients. Front Immunol. 2021;12:762341. doi:10.3389/fimmu.2021.762341
  • Baraibar I, Mirallas O, Saoudi N, et al. Combined treatment with immunotherapy-based strategies for MSS Metastatic Colorectal Cancer. Cancers. 2021;13(24):6311. doi:10.3390/cancers13246311
  • Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361–375. doi:10.1038/s41575-019-0126-x
  • Borelli B, Antoniotti C, Carullo M, Germani MM, Conca V, Masi G. Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) patients beyond microsatellite instability. Cancers. 2022;14(20):4974. doi:10.3390/cancers14204974
  • Li Y, Ma Y, Wu Z, et al. Tumor mutational burden predicting the efficacy of immune checkpoint inhibitors in colorectal cancer: a systematic review and meta-analysis. Front Immunol. 2021;12:751407. doi:10.3389/fimmu.2021.751407
  • Huang K, Lin B, Liu J, et al. Predicting colorectal cancer tumor mutational burden from histopatholog ical images and clinical information using multi-modal deep learning. Bioinformatics. 2022;38(22):5108–5115. doi:10.1093/bioinformatics/btac641
  • 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):325–340. doi:10.1038/nrclinonc.2018.29
  • Kim CW, Chon HJ, Kim C. Combination immunotherapies to overcome intrinsic resistance to checkpoint blockade in microsatellite stable colorectal cancer. Cancers. 2021;13(19):4906. doi:10.3390/cancers13194906
  • Fukuoka S, Hara H, Takahashi N, 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):2053–2061. doi:10.1200/JCO.19.03296
  • Li J, Cong L, Liu J, et al. The efficacy and safety of regorafenib in combination with anti-PD-1 antibody in refractory microsatellite stable metastatic colorectal cancer: a retrospective study. Front Oncol. 2020;10:594125. doi:10.3389/fonc.2020.594125
  • Cousin S, Cantarel C, Guegan JP, et al. Regorafenib-avelumab combination in patients with biliary tract cancer (REGOMUNE): a single-arm, open-label, phase II trial. Eur J Cancer. 2022;162:161–169. doi:10.1016/j.ejca.2021.11.012
  • Cousin S, Cantarel C, Guegan JP, 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):2139–2147. doi:10.1158/1078-0432.CCR-20-3416
  • Wang F, He MM, Yao YC, 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. doi:10.1016/j.xcrm.2021.100383
  • Cousin S, Bellera CA, Guégan JP, et al. REGOMUNE: a phase II study of regorafenib plus avelumab in solid tumors—Results of the non-MSI-H metastatic colorectal cancer (mCRC) cohort. J Clin Oncol. 2020;38(15_suppl):4019. doi:10.1200/JCO.2020.38.15_suppl.4019
  • Akin Telli T, Bregni G, Vanhooren M, Saude Conde R, Hendlisz A, Sclafani F. Regorafenib in combination with immune checkpoint inhibitors for mismatch repair proficient (pMMR)/microsatellite stable (MSS) colorectal cancer. Cancer Treat Rev. 2022;110:102460. doi:10.1016/j.ctrv.2022.102460
  • Gomez⁃Roca C, Yanez Ruiz E, Im S. LEAP-005: aphase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—results from the colorectal cancer cohort. J Clin Oncol. 2021;39(Suppl15):abstr3564. doi:10.1200/JCO.2021.39.15_suppl.3564
  • Mettu NB, Twohy E, Ou FS, et al. BACCI: a phase II randomized, double-blind, multicenter, placebo-controlled study of capecitabine (C) bevacizumab (B) plus atezolizumab (A) or placebo (P) in refractory metastatic colorectal cancer (mCRC): an ACCRU network study - ScienceDirect. Annals Oncol. 2019;30:v203.
  • Cremolini C, Rossini D, Antoniotti C. FOLFOXIRIplus bevacizumab(Bev) plus atezolizumab(Atezo) versus FOLFOXIRI plus bev as first-line treatment of unresectable metastatic colorectal cancer(mCRC) patients: results of the phase II randomized AtezoTRIBE study by GONO. Ann Oncol. 2021;32(Suppl 5):S1283–S1346. doi:10.1016/j.annonc.2021.08.2094
  • Zhou LN, Feng CX, Zhang Y, et al. The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis. J Gastrointest Oncol. 2022;13(3):1086–1096. doi:10.21037/jgo-22-207
  • Wang F, Dai G, Deng Y, et al. Efficacy and safety of chemotherapy combined with bevacizumab in Chinese patients with metastatic colorectal cancer: a prospective, multicenter, observational, non-interventional Phase IV trial. Chin J Cancer Res. 2021;33(4):490–499. doi:10.21147/j.issn.1000-9604.2021.04.06
  • Dell’Aquila E, Rossini D, Fulgenzi CAM, et al. Bone metastases are associated with worse prognosis in patients affected by metastatic colorectal cancer treated with doublet or triplet chemotherapy plus bevacizumab: a subanalysis of the TRIBE and TRIBE2 trials. ESMO Open. 2022;7(6):100606. doi:10.1016/j.esmoop.2022.100606
  • Guo Y, Zhang W, Ying J, Zhang Y, Li J. Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer. J Clin Oncol. 2021;39(15_suppl):2514. doi:10.1200/JCO.2021.39.15_suppl.2514
  • Bai Y, Xu N, An S, Chen W, Gao C, Zhang D. A phase ib trial of assessing the safety and preliminary efficacy of a combination therapy of geptanolimab (GB 226) plus fruquintinib in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39(15_suppl):e15551–e15551. doi:10.1200/JCO.2021.39.15_suppl.e15551
  • Sturrock M, Miller IS, Kang G, et al. Anti-angiogenic drug scheduling optimisation with application to colorectal cancer. Sci Rep. 2018;8(1):11182. doi:10.1038/s41598-018-29318-5
  • Lai E, Cascinu S, Scartozzi M. Are all anti-angiogenic drugs the same in the treatment of second-line metastatic colorectal cancer? Expert opinion on clinical practice. Front Oncol. 2021;11:637823. doi:10.3389/fonc.2021.637823
  • Cao M, Wang Y, Lu G, et al. Classical angiogenic signaling pathways and novel anti-angiogenic strategies for colorectal cancer. Curr Issues Mol Biol. 2022;44(10):4447–4471. doi:10.3390/cimb44100305
  • Doleschal B, Petzer A, Rumpold H. Current concepts of anti-EGFR targeting in metastatic colorectal cancer. Front Oncol. 2022;12:1048166. doi:10.3389/fonc.2022.1048166
  • Chu J, Fang X, Sun Z, et al. Non-coding RNAs regulate the resistance to anti-EGFR therapy in colorectal cancer. Front Oncol. 2021;11:801319. doi:10.3389/fonc.2021.801319
  • Park YL, Kim HP, Ock CY, et al. EMT-mediated regulation of CXCL1/5 for resistance to anti-EGFR therapy in colorectal cancer. Oncogene. 2022;41(14):2026–2038. doi:10.1038/s41388-021-01920-4
  • Janani B, Vijayakumar M, Priya K, et al. EGFR-based targeted therapy for colorectal cancer-promises and challenges. Vaccines. 2022;10(4). doi:10.3390/vaccines10040499
  • Zhang W, Han X, Yang L, et al. Safety, pharmacokinetics and efficacy of SCT200, an anti-EGFR monoclonal antibody in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer: a phase I dose-escalation and dose-expansion study. BMC Cancer. 2022;22(1):1104. doi:10.1186/s12885-022-10147-9
  • Lee MS, Loehrer PJ, Imanirad I, et al. Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39(3_suppl):7. doi:10.1200/JCO.2021.39.3_suppl.7
  • Stein A, Binder M, Goekkurt E, et al. Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): final results of the phase II AVETUX trial (AIO-KRK-0216). J Clin Oncol. 2020;38(4_suppl):96. doi:10.1200/JCO.2020.38.4_suppl.96
  • Boland PM, Hutson A, Maguire O, Minderman H, Fountzilas C, Iyer RV. A phase Ib/II study of cetuximab and pembrolizumab in RAS-wt mCRC. J Clin Oncol. 2018;36(4_suppl):834. doi:10.1200/JCO.2018.36.4_suppl.834
  • Cooper ZA, Reuben A, Austin-Breneman J, Wargo JA. Does it MEK a difference? Understanding immune effects of targeted therapy. Clin Cancer Res. 2015;21(14):3102–3104. doi:10.1158/1078-0432.CCR-15-0363
  • Goldman C, Tchack J, Robinson EM, et al. Outcomes in melanoma patients treated with BRAF/MEK-directed therapy or immune checkpoint inhibition stratified by clinical trial versus standard of care. Oncology. 2017;93(3):164–176. doi:10.1159/000475715
  • Buhle A, Johnson N, Grider D, Phillips M. Early onset drug-induced hypersensitivity syndrome with lymphopenia, hepatitis, and normal eosinophils induced by BRAF/MEK inhibitor after immune checkpoint inhibitor therapy. Dermatol Online J. 2022;28(1). doi:10.5070/D328157062
  • Schröder C, Lawrance M, Li C, et al. Building external control arms from patient-level electronic health record data to replicate the randomized IMblaze370 control arm in metastatic colorectal cancer. JCO Clin Cancer Infor. 2021;(5):450–458. doi:10.1200/cci.20.00149
  • Schuch G, Kobold S, Bokemeyer C. Evolving role of cetuximab in the treatment of colorectal cancer. Cancer Manag Res. 2009;1:79–88. doi:10.2147/CMAR.S4750
  • Bendell JC, Kopetz S, Middleton MR, et al. Phase 1b/2 study of binimetinib (BINI) in combination with nivolumab (NIVO) or NIVO plus ipilimumab (IPI) in patients (pts) with previously treated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) with RAS mutation. J Clin Oncol. 2018;36(4_suppl):TPS870–TPS870. doi:10.1200/JCO.2018.36.4_suppl.TPS870
  • Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–2538. doi:10.1200/JCO.21.02752
  • Corcoran R, Giannakis M, Allen J. SO-26 Clinical efficacy of combined BRAF, MEK, and PD −1 inhibition in BRAFV600E colorectal cancer patients. Ann Oncol. 2020;31:S226–S227. doi:10.1016/j.annonc.2020.04.041
  • Xu T, Wang X, Xin Y, et al. Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: a phase II single-arm study and exploratory biomarker analysis. Cancer Res Treat. 2022;55:626–635. doi:10.4143/crt.2022.1058
  • Strickler JH, Ng K, Cercek A, et al. MOUNTAINEER: open-label, phase II study of tucatinib combined with trastuzumab for HER2-positive metastatic colorectal cancer (SGNTUC-017, trial in progress). J Clin Oncol. 2021;39(3_suppl):TPS153–TPS153. doi:10.1200/JCO.2021.39.3_suppl.TPS153
  • Suh K, Carlson JJ, Xia F, Williamson TE, Sullivan SD. The potential long-term comparative effectiveness of larotrectinib versus entrectinib for treatment of metastatic TRK fusion colorectal cancer. J Clin Oncol. 2022;40(4_suppl):40. doi:10.1200/JCO.2022.40.4_suppl.040
  • Yamada N, Karasawa T, Wakiya T, et al. Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: potential role of ferroptosis. Am J Transplant. 2020;20(6):1606–1618. doi:10.1111/ajt.15773
  • Anne H, Harme H, Kersten C. Repeat sequential oxaliplatin⁃based chemotherapy (FLOX) and nivolumab versus FLOX alone as first⁃line treatment of microsatellite⁃stable (MSS) metastatic colorectal cancer (mCRC): initial results from the randomized METIMMOX study. J Clin Oncol. 2021;39(Suppl15):abstr3556. doi:10.1200/JCO.2021.39.15_suppl.3556
  • Tabernero J, Grothey A, Arnold D. Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal⁃seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer. J Clin Oncol. 2021;39(Suppl 15):S3570. doi:10.1200/JCO.2021.39.15_suppl.3570
  • Xue M, Tian Y, Sui Y, et al. Protective effect of fucoidan against iron overload and ferroptosis-induced liver injury in rats exposed to alcohol. Bio Pharmaco. 2022;153:113402. doi:10.1016/j.biopha.2022.113402
  • Voronova V, Vislobokova A, Mutig K, et al. Combination of immune checkpoint inhibitors with radiation therapy in cancer: a hammer breaking the wall of resistance. Front Oncol. 2022;12:1035884. doi:10.3389/fonc.2022.1035884
  • Parikh AR, Clark JW, Wo JY-L, et al. A phase II study of ipilimumab and nivolumab with radiation in microsatellite stable (MSS) metastatic colorectal adenocarcinoma (mCRC). J Clin Oncol. 2019;37(15_suppl):3514. doi:10.1200/JCO.2019.37.15_suppl.3514
  • Salvatore L, Bensi M, Corallo S, et al. Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): the AVANA study. J Clin Oncol. 2021;39(15_suppl):3511. doi:10.1200/JCO.2021.39.15_suppl.3511
  • Tamberi S, Grassi E, Zingaretti C, et al. A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study final results. J Clin Oncol. 2022;40(17_suppl):LBA3513–LBA3513. doi:10.1200/JCO.2022.40.17_suppl.LBA3513
  • Michael M, Wong R, Gill SS, et al. Phase II trial PD-L1/PD-1 blockade avelumab with chemoradiotherapy for locally advanced resectable T3B-4/N1-2 rectal cancer: the Ave-Rec trial. J Clin Oncol. 2019;37(15_suppl):TPS3622–TPS3622. doi:10.1200/JCO.2019.37.15_suppl.TPS3622
  • Wu Q, Hu X, Zhang X, et al. Single-cell transcriptomics of peripheral blood reveals anti-tumor systemic immunity induced by oncolytic virotherapy. Theranostics. 2022;12(17):7371–7389. doi:10.7150/thno.74075
  • Nelson A, Gebremeskel S, Lichty BD, Johnston B. Natural killer T cell immunotherapy combined with IL-15-expressing oncolytic virotherapy and PD-1 blockade mediates pancreatic tumor regression. J Immunother Cancer. 2022;10(3). doi:10.1136/jitc-2021-003923
  • Svensson-Arvelund J, Cuadrado-Castano S, Pantsulaia G, et al. Expanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity. Nat Commun. 2022;13(1):7149. doi:10.1038/s41467-022-34791-8
  • Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2018;174(4):1031–1032. doi:10.1016/j.cell.2018.07.035
  • Monge B MC, Xie C, Steinberg SM, et al. A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer. J Clin Oncol. 2020;38(4_suppl):117. doi:10.1200/JCO.2020.38.4_suppl.117
  • Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011;17(11):3520–3526. doi:10.1158/1078-0432.CCR-10-3126
  • de Weger VA, Turksma AW, Voorham QJ, et al. Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin Cancer Res. 2012;18(3):882–889. doi:10.1158/1078-0432.CCR-11-1716
  • Uyl-de Groot CA, Vermorken JB, Hanna MG Jr, et al. Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits. Vaccine. 2005;23(17–18):2379–2387. doi:10.1016/j.vaccine.2005.01.015
  • Hubbard JM, Cremolini C, Graham RP, et al. A phase I study of PolyPEPI1018 vaccine plus maintenance therapy in patients with metastatic colorectal cancer with a predictive biomarker (OBERTO). J Clin Oncol. 2019;37(15_suppl):3557. doi:10.1200/JCO.2019.37.15_suppl.3557
  • Hubbard JM, Cremolini C, Graham RP, et al. Evaluation of safety, immunogenicity, and preliminary efficacy of PolyPEPI1018 off-the-shelf vaccine with fluoropyrimidine/bevacizumab maintenance therapy in metastatic colorectal cancer (mCRC) patients. J Clin Oncol. 2020;38(15_suppl):4048. doi:10.1200/JCO.2020.38.15_suppl.4048
  • O’Leary K. CAR T cells beyond cancer. Nat Med. 2022;28(12):2450. doi:10.1038/s41591-022-02150-1
  • Bailey SR, Berger TR, Graham C, Larson RC, Maus MV. Four challenges to CAR T cells breaking the glass ceiling. Eur J Immunol. 2022;e2250039. doi:10.1002/eji.202250039
  • Ghazi B, El Ghanmi A, Kandoussi S, Ghouzlani A, Badou A. CAR T-cells for colorectal cancer immunotherapy: ready to go? Front Immunol. 2022;13:978195. doi:10.3389/fimmu.2022.978195
  • Wang L, Zhang G, Shen J, Shen Y, Cai G, Liu Y. Elevated CEA and CA 19-9 levels within the normal ranges increase the likelihood of CRC recurrence in the Chinese han population. Appl Bionics Biomech. 2022;2022:8666724. doi:10.1155/2022/8666724
  • Koyel B, Priyabrata D, Rittwika B, et al. Deterministic role of CEA and MSI status in predicting outcome of CRC patients: a perspective study amongst hospital attending Eastern Indian Populations. Indian J Surg Oncol. 2017;8(4):462–468. doi:10.1007/s13193-017-0651-4
  • Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19(3):620–626. doi:10.1038/mt.2010.272
  • Katz SC, Burga RA, McCormack E, 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):3149–3159. doi:10.1158/1078-0432.CCR-14-1421
  • Prenen H, Dekervel J, Hendlisz A, et al. Updated data from alloSHRINK phase I first-in-human study evaluating CYAD-101, an innovative non-gene edited allogeneic CAR-T in mCRC. J Clin Oncol. 2021;39(3_suppl):74. doi:10.1200/JCO.2021.39.3_suppl.74
  • Cui J, Chen N, Pu C, et al. A phase 1 dose-escalation study of GCC19 CART a novel coupled CAR therapy for subjects with metastatic colorectal cancer. J Clin Oncol. 2022;40(16_suppl):3582. doi:10.1200/JCO.2022.40.16_suppl.3582
  • Morse MA, Hochster H, Benson A. Perspectives on treatment of metastatic colorectal cancer with immune checkpoint inhibitor therapy. Oncologist. 2020;25(1):33–45. doi:10.1634/theoncologist.2019-0176
  • Peng X, Zhao G, Lin J, Qu J, Zhang Y, Li C. Phospholipase Cgamma2 is critical for Ca(2+) flux and cytokine production in anti-fungal innate immunity of human corneal epithelial cells. BMC Ophthalmol. 2018;18(1):170. doi:10.1186/s12886-018-0847-6
  • Dai W, Li Y, Sun W, et al. Silencing of OGDHL promotes liver cancer metastasis by enhancing hypoxia inducible factor 1 alpha protein stability. Cancer Sci. 2022. doi:10.1111/cas.15540
  • Yorita N, Yuge R, Takigawa H, et al. Stromal reaction inhibitor and immune-checkpoint inhibitor combination therapy attenuates excluded-type colorectal cancer in a mouse model. Cancer Lett. 2021;498:111–120. doi:10.1016/j.canlet.2020.10.041