Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects
Abstract
:1. Introduction
2. Search Strategy and Selection Criteria
3. The Immune Microenvironment in Colorectal Cancer (CRC)
3.1. Immune Cells Involved in Tumor Suppression in the TME
3.2. Immune Cells of TME Involved in Tumor Progression
4. Immune Checkpoint Molecules
4.1. CTLA-4
4.2. PD-1/PD-L1
4.3. LAG-3
4.4. TIM-3
5. Immunotherapy with Immune Checkpoint Inhibitors (ICIs)
5.1. Anti-CTLA-4
5.2. Anti-PD-1
5.3. Anti-PD-L1
5.4. Anti-LAG-3
5.5. Anti-TIM-3
5.6. Double Blockade of Immune Checkpoints
6. Combination of Immune Checkpoint Inhibitors with Other Immunotherapies
7. Combination of Immune Checkpoint Inhibitors with Conventional Treatments
7.1. Immune Checkpoint Inhibitors plus Radiotherapy
7.2. Immune Checkpoint Inhibitors plus Chemotherapy
8. Adverse Effects
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
- Derakhshani, A.; Hashemzadeh, S.; Asadzadeh, Z.; Shadbad, M.A.; Rasibonab, F.; Safarpour, H.; Jafarlou, V.; Solimando, A.G.; Racanelli, V.; Singh, P.K.; et al. Cytotoxic T-Lymphocyte Antigen-4 in Colorectal Cancer: Another Therapeutic Side of Capecitabine. Cancers 2021, 137, 2414. [Google Scholar] [CrossRef]
- Asadzadeh, Z.; Mansoori, B.; Mohammadi, A.; Kazemi, T.; Mokhtarzadeh, A.; Shanehbandi, D.; Hemmat, N.; Derakhshani, A.; Brunetti, O.; Safaei, S.; et al. The combination effect of Prominin1 (CD133) suppression and Oxaliplatin treatment in colorectal cancer therapy. Biomed. Pharmacother. 2021, 137, 111364. [Google Scholar] [CrossRef]
- Dekker, E.; Tanis, P.J.; Vleugels, J.; Kasi, P.M.; Wallace, M.B. Risk factors. Lancet 2019, 394, 1467–1480. [Google Scholar] [CrossRef]
- Venook, A. Gastrointestinal Cancer. Oncologist 2005, 10, 250–261. [Google Scholar] [CrossRef]
- Hammond, W.A.; Swaika, A.; Mody, K. Pharmacologic resistance in colorectal cancer: A review. Ther. Adv. Med Oncol. 2016, 8, 57–84. [Google Scholar] [CrossRef] [Green Version]
- Tsai, H.-F.; Hsu, P.-N. Cancer immunotherapy by targeting immune checkpoints: Mechanism of T cell dysfunction in cancer immunity and new therapeutic targets. J. Biomed. Sci. 2017, 24, 35. [Google Scholar] [CrossRef]
- Ganesh, K.; Stadler, Z.K.; Cercek, A.; Mendelsohn, R.B.; Shia, J.; Segal, N.H.; Diaz, L.A. Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 361–375. [Google Scholar] [CrossRef]
- Derakhshani, A.; Rostami, Z.; Safarpour, H.; Shadbad, M.A.; Nourbakhsh, N.S.; Argentiero, A.; Taefehshokr, S.; Tabrizi, N.J.; Kooshkaki, O.; Astamal, R.V.; et al. From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy. Molecules 2021, 26, 2278. [Google Scholar] [CrossRef]
- Kooshkaki, O.; Derakhshani, A.; Safarpour, H.; Najafi, S.; Vahedi, P.; Brunetti, O.; Torabi, M.; Lotfinejad, P.; Paradiso, A.V.; Racanelli, V.; et al. The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers. Int. J. Mol. Sci. 2020, 21, 5034. [Google Scholar] [CrossRef]
- Safarzadeh, A.; Alizadeh, M.; Beyranvand, F.; Jozaaee, R.F.; Hajiasgharzadeh, K.; Baghbanzadeh, A.; Derakhshani, A.; Argentiero, A.; Baradaran, B.; Silvestris, N. Varied functions of immune checkpoints during cancer metastasis. Cancer Immunol. Immunother. 2021, 70, 569–588. [Google Scholar] [CrossRef]
- Demlova, R.; Valík, D.; Obermannova, R.; ZdraŽilová-Dubská, L. The Safety of Therapeutic Monoclonal Antibodies: Implications for Cancer Therapy Including Immuno-Checkpoint Inhibitors. Physiol. Res. 2016, 65, S455–S462. [Google Scholar] [CrossRef]
- Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef] [Green Version]
- Kooshkaki, O.; Derakhshani, A.; Hosseinkhani, N.; Torabi, M.; Safaei, S.; Brunetti, O.; Racanelli, V.; Silvestris, N.; Baradaran, B. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials. Int. J. Mol. Sci. 2020, 21, 4427. [Google Scholar] [CrossRef]
- Hosseinkhani, N.; Derakhshani, A.; Kooshkaki, O.; Abdoli Shadbad, M.; Hajiasgharzadeh, K.; Baghbanzadeh, A.; Safarpour, H.; Mokhtarzadeh, A.; Brunetti, O.; Yue, S.C.; et al. Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies? Int. J. Mol. Sci. 2020, 21, 8305. [Google Scholar] [CrossRef]
- Hosseinkhani, N.; Derakhshani, A.; Shadbad, M.A.; Argentiero, A.; Racanelli, V.; Kazemi, T.; Mokhtarzadeh, A.; Brunetti, O.; Silvestris, N.; Baradaran, B. The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead. Front. Immunol. 2021, 12, 1797. [Google Scholar] [CrossRef]
- Rhoads, C. Paul Ehrlich and the cancer problem. Ann. N. Y. Acad. Sci. 1954, 59, 190–197. [Google Scholar] [CrossRef]
- Ribatti, D. The concept of immune surveillance against tumors: The first theories. Oncotarget 2017, 8, 7175–7180. [Google Scholar] [CrossRef] [Green Version]
- O’Donnell, J.S.; Teng, M.W.L.; Smyth, M.J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 2019, 16, 151–167. [Google Scholar] [CrossRef]
- Xiong, Y.; Wang, Y.; Tiruthani, K. Tumor immune microenvironment and nano-immunotherapeutics in colorectal cancer. Nanomed. Nanotechnol. Biol. Med. 2019, 21, 102034. [Google Scholar] [CrossRef]
- Whiteside, T.L. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008, 27, 5904–5912. [Google Scholar] [CrossRef] [Green Version]
- Koi, M.; Carethers, J.M. The colorectal cancer immune microenvironment and approach to immunotherapies. Future Oncol. 2017, 13, 1633–1647. [Google Scholar] [CrossRef]
- Pietras, K.; Östman, A. Hallmarks of cancer: Interactions with the tumor stroma. Exp. Cell Res. 2010, 316, 1324–1331. [Google Scholar] [CrossRef]
- Tape, C.J. The Heterocellular Emergence of Colorectal Cancer. Trends Cancer 2017, 3, 79–88. [Google Scholar] [CrossRef] [Green Version]
- Khosravi, N.; Mokhtarzadeh, A.; Baghbanzadeh, A.; Hajiasgharzadeh, K.; Shahgoli, V.K.; Hemmat, N.; Safarzadeh, E.; Baradaran, B. Immune checkpoints in tumor microenvironment and their relevance to the development of cancer stem cells. Life Sci. 2020, 256, 118005. [Google Scholar] [CrossRef]
- Quante, M.; Varga, J.; Wang, T.C.; Greten, F.R. The Gastrointestinal Tumor Microenvironment. Gastroenterology 2013, 145, 63–78. [Google Scholar] [CrossRef] [Green Version]
- Markman, J.L.; Shiao, S.L. Impact of the immune system and immunotherapy in colorectal cancer. J. Gastrointest. Oncol. 2015, 6, 208–223. [Google Scholar] [CrossRef]
- Sconocchia, G.; Eppenberger, S.; Spagnoli, G.C.; Tornillo, L.; Droeser, R.; Caratelli, S.; Ferrelli, F.; Coppola, A.; Arriga, R.; Lauro, D.; et al. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology 2014, 3, e952197. [Google Scholar] [CrossRef] [Green Version]
- Kather, J.N.; Halama, N. Harnessing the innate immune system and local immunological microenvironment to treat colorectal cancer. Br. J. Cancer 2019, 120, 871–882. [Google Scholar] [CrossRef] [Green Version]
- Colangelo, T.; Polcaro, G.; Muccillo, L.; D’Agostino, G.; Rosato, V.; Ziccardi, P.; Lupo, A.; Mazzoccoli, G.; Sabatino, L.; Colantuoni, V. Friend or foe? The tumour microenvironment dilemma in colorectal cancer. Biochim. Biophys. Acta Rev. Cancer 2017, 1867, 1–18. [Google Scholar] [CrossRef]
- Yu, P.; Fu, Y.-X. Tumor-infiltrating T lymphocytes: Friends or foes? Lab. Investig. 2006, 86, 231–245. [Google Scholar] [CrossRef] [Green Version]
- Thommen, D.S.; Schumacher, T.N. T Cell Dysfunction in Cancer. Cancer Cell 2018, 33, 547–562. [Google Scholar] [CrossRef] [Green Version]
- Zarour, H.M. Reversing T-cell Dysfunction and Exhaustion in Cancer. Clin. Cancer Res. 2016, 22, 1856–1864. [Google Scholar] [CrossRef] [Green Version]
- Gao, D.; Mittal, V. The role of bone-marrow-derived cells in tumor growth, metastasis initiation and progression. Trends Mol. Med. 2009, 15, 333–343. [Google Scholar] [CrossRef]
- Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253–268. [Google Scholar] [CrossRef] [Green Version]
- Chaudhary, B.; Elkord, E. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. Vaccines 2016, 4, 28. [Google Scholar] [CrossRef] [Green Version]
- Safarzadeh, E.; Asadzadeh, Z.; Safaei, S.; Hatefi, A.; Derakhshani, A.; Giovannelli, F.; Brunetti, O.; Silvestris, N.; Baradaran, B. MicroRNAs and lncRNAs—A New Layer of Myeloid-Derived Suppressor Cells Regulation. Front. Immunol. 2020, 11, 572323. [Google Scholar] [CrossRef]
- Cui, G.; Yuan, A.; Li, Z.; Goll, R.; Florholmen, J. ST2 and regulatory T cells in the colorectal adenoma/carcinoma microenvironment: Implications for diseases progression and prognosis. Sci. Rep. 2020, 10, 5892. [Google Scholar] [CrossRef] [Green Version]
- Salama, P.; Phillips, M.; Grieu, F.; Morris, M.; Zeps, N.; Joseph, D.; Platell, C.; Iacopetta, B. Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer. J. Clin. Oncol. 2009, 27, 186–192. [Google Scholar] [CrossRef]
- Wang, D.; Wang, X.; Si, M.; Yang, J.; Sun, S.; Wu, H.; Cui, S.; Qu, X.; Yu, X. Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages. Cancer Lett. 2020, 474, 36–52. [Google Scholar] [CrossRef]
- Toor, S.M.; Elkord, E. Myeloid-Derived Suppressor Cells. eLS 2015. [Google Scholar] [CrossRef]
- Khaled, Y.S.; Ammori, B.J.; Elkord, E. Myeloid-derived suppressor cells in cancer: Recent progress and prospects. Immunol. Cell Biol. 2013, 91, 493–502. [Google Scholar] [CrossRef]
- Sun, H.-L.; Zhou, X.; Xue, Y.-F.; Wang, K.; Shen, Y.-F.; Mao, J.-J.; Guo, H.-F.; Miao, Z.-N. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J. Gastroenterol. 2012, 18, 3303–3309. [Google Scholar] [CrossRef]
- Zhang, B.; Wang, Z.; Wu, L.; Zhang, M.; Li, W.; Ding, J.-H.; Zhu, J.; Wei, H.; Zhao, K. Circulating and Tumor-Infiltrating Myeloid-Derived Suppressor Cells in Patients with Colorectal Carcinoma. PLoS ONE 2013, 8, e57114. [Google Scholar] [CrossRef] [Green Version]
- Farhood, B.; Najafi, M.; Mortezaee, K. Cancer-associated fibroblasts: Secretions, interactions, and therapy. J. Cell. Biochem. 2019, 120, 2791–2800. [Google Scholar] [CrossRef]
- Hawinkels, L.; Paauwe, M.; Verspaget, H.W.; Wiercinska, E.; Van Der Zon, J.M.; Van Der Ploeg, K.; Koelink, P.J.; Lindeman, J.H.N.; Mesker, W.; Dijke, P.T.; et al. Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts. Oncogene 2014, 33, 97–107. [Google Scholar] [CrossRef] [Green Version]
- Calon, A.; Espinet, E.; Palomo-Ponce, S.; Tauriello, D.V.F.; Iglesias, M.; Céspedes, M.V.; Sevillano, M.; Nadal, C.; Jung, P.; Zhang, X.H.-F.; et al. Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation. Cancer Cell 2012, 22, 571–584. [Google Scholar] [CrossRef] [Green Version]
- Passardi, A.; Canale, M.; Valgiusti, M.; Ulivi, P. Immune Checkpoints as a Target for Colorectal Cancer Treatment. Int. J. Mol. Sci. 2017, 18, 1324. [Google Scholar] [CrossRef]
- Naidoo, J.; Page, D.B.; Wolchok, J.D. Immune Checkpoint Blockade. Hematol. Oncol. Clin. N. Am. 2014, 28, 585–600. [Google Scholar] [CrossRef]
- Dyck, L.; Mills, K.H. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur. J. Immunol. 2017, 47, 765–779. [Google Scholar] [CrossRef]
- Marcucci, F.; Rumio, C.; Corti, A. Tumor cell-associated immune checkpoint molecules—Drivers of malignancy and stemness. Biochim. Biophys. Acta Rev. Cancer 2017, 1868, 571–583. [Google Scholar] [CrossRef]
- Marisa, L.; Svrcek, M.; Collura, A.; Becht, E.; Cervera, P.; Wanherdrick, K.; Buhard, O.; Goloudina, A.; Jonchère, V.; Selves, J.; et al. The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors. J. Natl. Cancer Inst. 2018, 110, 68–77. [Google Scholar] [CrossRef]
- Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res. 2019, 38, 1–12. [Google Scholar] [CrossRef]
- Walker, L.S.; Sansom, D.M. Confusing signals: Recent progress in CTLA-4 biology. Trends Immunol. 2015, 36, 63–70. [Google Scholar] [CrossRef] [Green Version]
- Harton, J.; Jin, L.; Hahn, A.; Drake, J. Immunological Functions of the Membrane Proximal Region of MHC Class II Molecules. F1000Research 2016, 5, 368. [Google Scholar] [CrossRef] [Green Version]
- Ganesan, A.; Moon, T.C.; Barakat, K.H. Revealing the atomistic details behind the binding of B7–1 to CD28 and CTLA-4: A comprehensive protein-protein modelling study. Biochim. Biophys. Acta Gen. Subj. 2018, 1862, 2764–2778. [Google Scholar] [CrossRef]
- Zenke, S.; Palm, M.M.; Braun, J.; Gavrilov, A.; Meiser, P.; Böttcher, J.P.; Beyersdorf, N.; Ehl, S.; Gerard, A.; Lämmermann, T.; et al. Quorum Regulation via Nested Antagonistic Feedback Circuits Mediated by the Receptors CD28 and CTLA-4 Confers Robustness to T Cell Population Dynamics. Immunity 2020, 52, 313–327.e7. [Google Scholar] [CrossRef]
- Alegre, M.-L.; Frauwirth, K.A.; Thompson, C.B. T-cell regulation by CD28 and CTLA-4. Nat. Rev. Immunol. 2001, 1, 220–228. [Google Scholar] [CrossRef]
- Qin, S.; Xu, L.; Yi, M.; Yu, S.; Wu, K.; Luo, S. Novel immune checkpoint targets: Moving beyond PD-1 and CTLA-4. Mol. Cancer 2019, 18, 1–14. [Google Scholar] [CrossRef]
- Paterson, A.M.; Lovitch, S.B.; Sage, P.T.; Juneja, V.R.; Lee, Y.; Trombley, J.D.; Arancibia-Cárcamo, C.V.; Sobel, R.A.; Rudensky, A.Y.; Kuchroo, V.K.; et al. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J. Exp. Med. 2015, 212, 1603–1621. [Google Scholar] [CrossRef]
- Chang, L.-S.; Barroso-Sousa, R.; Tolaney, S.M.; Hodi, F.S.; Kaiser, U.B.; Min, L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr. Rev. 2019, 40, 17–65. [Google Scholar] [CrossRef] [Green Version]
- 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, 3887–3895. [Google Scholar] [CrossRef]
- Derakhshani, A.; Asadzadeh, Z.; Safarpour, H.; Leone, P.; Shadbad, M.A.; Heydari, A.; Baradaran, B.; Racanelli, V. Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs. J. Pers. Med. 2021, 11, 721. [Google Scholar] [CrossRef]
- Dong, Y.; Sun, Q.; Zhang, X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget 2017, 8, 2171–2186. [Google Scholar] [CrossRef] [Green Version]
- Berger, K.N.; Pu, J.J. PD-1 pathway and its clinical application: A 20 year journey after discovery of the complete human PD-1 gene. Gene 2018, 638, 20–25. [Google Scholar] [CrossRef]
- Arasanz, H.; Gato-Cañas, M.; Zuazo, M.; Ibañez-Vea, M.; Breckpot, K.; Kochan, G.; Escors, D. PD1 signal transduction pathways in T cells. Oncotarget 2017, 8, 51936. [Google Scholar] [CrossRef] [Green Version]
- Alsaab, H.O.; Sau, S.; Alzhrani, R.; Tatiparti, K.; Bhise, K.; Kashaw, S.K.; Iyer, A.K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front. Pharmacol. 2017, 8, 561. [Google Scholar] [CrossRef]
- Kinter, A.L.; Godbout, E.J.; McNally, J.P.; Sereti, I.; Roby, G.A.; O’Shea, M.A.; Fauci, A.S. The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands. J. Immunol. 2008, 181, 6738–6746. [Google Scholar] [CrossRef]
- Constantinidou, A.; Alifieris, K.; Trafalis, D.T. Targeting Programmed Cell Death -1 (PD-1) and Ligand (PD-L1): A new era in cancer active immunotherapy. Pharmacol. Ther. 2019, 194, 84–106. [Google Scholar] [CrossRef]
- Taube, J.M.; Klein, A.; Brahmer, J.R.; Xu, H.; Pan, X.; Kim, J.H.; Chen, L.; Pardoll, D.M.; Topalian, S.L.; Anders, R.A. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti–PD-1 therapy. Clin. Cancer Res. 2014, 20, 5064–5074. [Google Scholar] [CrossRef] [Green Version]
- Jiang, X.; Wang, J.; Deng, X.; Xiong, F.; Ge, J.; Xiang, B.; Wu, X.; Ma, J.; Zhou, M.; Li, X.; et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol. Cancer 2019, 18, 1–17. [Google Scholar] [CrossRef] [Green Version]
- Gao, L.; Guo, Q.; Li, X.; Yang, X.; Ni, H.; Wang, T.; Zhao, Q.; Liu, H.; Xing, Y.; Xi, T.; et al. MiR-873/PD-L1 axis regulates the stemness of breast cancer cells. EBioMedicine 2019, 41, 395–407. [Google Scholar] [CrossRef] [Green Version]
- Massari, F.; Santoni, M.; Ciccarese, C.; Santini, D.; Alfieri, S.; Martignoni, G.; Brunelli, M.; Piva, F.; Berardi, R.; Montironi, R.; et al. PD-1 blockade therapy in renal cell carcinoma: Current studies and future promises. Cancer Treat. Rev. 2015, 41, 114–121. [Google Scholar] [CrossRef]
- Merelli, B.; Massi, D.; Cattaneo, L.; Mandalà, M. Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities. Crit. Rev. Oncol. Hematol. 2014, 89, 140–165. [Google Scholar] [CrossRef] [Green Version]
- Yaghoubi, N.; Soltani, A.; Ghazvini, K.; Hassanian, S.M.; Hashemy, S.I. PD-1/PD-L1 blockade as a novel treatment for colorectal cancer. Biomed. Pharmacother. 2019, 110, 312–318. [Google Scholar] [CrossRef]
- Perez-Santos, M.; Anaya-Ruiz, M.; Cebada, J.; Bandala, C.; Landeta, G.; Martínez-Morales, P.L.; Villa-Ruano, N. LAG-3 antagonists by cancer treatment: A patent review. Expert Opin. Ther. Pat. 2019, 29, 643–651. [Google Scholar] [CrossRef]
- Triebel, F.; Jitsukawa, S.; Baixeras, E.; Roman-Roman, S.; Genevee, C.; Viegas-Pequignot, E.; Hercend, T. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 1990, 171, 1393–1405. [Google Scholar] [CrossRef] [Green Version]
- Andrews, L.P.; Marciscano, A.E.; Drake, C.G.; Vignali, D.A.A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 2017, 276, 80–96. [Google Scholar] [CrossRef]
- Puhr, H.C.; Ilhan-Mutlu, A. New emerging targets in cancer immunotherapy: The role of LAG3. ESMO Open 2019, 4, e000482. [Google Scholar] [CrossRef] [Green Version]
- Maeda, T.K.; Sugiura, D.; Okazaki, I.-M.; Maruhashi, T.; Okazaki, T. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J. Biol. Chem. 2019, 294, 6017–6026. [Google Scholar] [CrossRef]
- Solinas, C.; Migliori, E.; De Silva, P.; Willard-Gallo, K. LAG3: The Biological Processes That Motivate Targeting This Immune Checkpoint Molecule in Human Cancer. Cancers 2019, 11, 1213. [Google Scholar] [CrossRef] [Green Version]
- Anderson, A.C.; Joller, N.; Kuchroo, V.K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016, 44, 989–1004. [Google Scholar] [CrossRef] [Green Version]
- Liang, B.; Workman, C.; Lee, J.; Chew, C.; Dale, B.M.; Colonna, L.; Flores, M.; Li, N.; Schweighoffer, E.; Greenberg, S.; et al. Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II. J. Immunol. 2008, 180, 5916–5926. [Google Scholar] [CrossRef] [Green Version]
- He, Y.; Rivard, C.J.; Rozeboom, L.; Yu, H.; Ellison, K.; Kowalewski, A.; Zhou, C.; Hirsch, F.R. Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Sci. 2016, 107, 1193–1197. [Google Scholar] [CrossRef]
- Dong, Y.; Li, X.; Zhang, L.; Zhu, Q.; Chen, C.; Bao, J.; Chen, Y. CD4+ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B. BMC Immunol. 2019, 20, 27. [Google Scholar] [CrossRef]
- Long, L.; Zhang, X.; Chen, F.; Pan, Q.; Phiphatwatchara, P.; Zeng, Y.; Chen, H. The promising immune checkpoint LAG-3: From tumor microenvironment to cancer immunotherapy. Genes Cancer 2018, 9, 176–189. [Google Scholar] [CrossRef] [Green Version]
- Zhou, G.; Noordam, L.; Sprengers, D.; Doukas, M.; Boor, P.P.C.; Van Beek, A.A.; Erkens, R.; Mancham, S.; Grünhagen, D.; Menon, A.G.; et al. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology 2018, 7, e1448332. [Google Scholar] [CrossRef]
- Freeman, G.J.; Casasnovas, J.M.; Umetsu, D.T.; DeKruyff, R.H. TIM genes: A family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol. Rev. 2010, 235, 172–189. [Google Scholar] [CrossRef] [Green Version]
- He, Y.; Cao, J.; Zhao, C.; Li, X.; Zhou, C.; Hirsch, F.R. TIM-3, a promising target for cancer immunotherapy. OncoTargets Ther. 2018, 11, 7005–7009. [Google Scholar] [CrossRef] [Green Version]
- Chae, S.-C.; Song, J.-H.; Pounsambath, P.; Yuan, H.-Y.; Lee, J.-H.; Kim, J.-J.; Lee, Y.-C.; Chung, H.-T. Molecular variations in Th1-specific cell surface gene Tim-3. Exp. Mol. Med. 2004, 36, 274–278. [Google Scholar] [CrossRef] [Green Version]
- Holderried, T.A.; De Vos, L.; Bawden, E.G.; Vogt, T.J.; Dietrich, J.; Zarbl, R.; Bootz, F.; Kristiansen, G.; Brossart, P.; Landsberg, J.; et al. Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma. Clin. Epigenetics 2019, 11, 1–15. [Google Scholar] [CrossRef]
- Bi, S.; Earl, L.A.; Jacobs, L.; Baum, L.G. Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways. J. Biol. Chem. 2008, 283, 12248–12258. [Google Scholar] [CrossRef] [Green Version]
- Fujita, K.; Iwama, H.; Oura, K.; Tadokoro, T.; Samukawa, E.; Sakamoto, T.; Nomura, T.; Tani, J.; Yoneyama, H.; Morishita, A.; et al. Cancer Therapy Due to Apoptosis: Galectin-9. Int. J. Mol. Sci. 2017, 18, 74. [Google Scholar] [CrossRef] [Green Version]
- Gorman, J.V.; Colgan, J.D. Regulation of T cell responses by the receptor molecule Tim-3. Immunol. Res. 2014, 59, 56–65. [Google Scholar] [CrossRef] [Green Version]
- Zhu, C.; Anderson, A.C.; Schubart, A.; Xiong, H.; Imitola, J.; Khoury, S.J.; Zheng, X.X.; Strom, T.B.; Kuchroo, V.K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 2005, 6, 1245–1252. [Google Scholar] [CrossRef]
- Cheng, L.; Ruan, Z. Tim-3 and Tim-4 as the potential targets for antitumor therapy. Hum. Vaccines Immunother. 2015, 11, 2458–2462. [Google Scholar] [CrossRef]
- Wolf, Y.; Anderson, A.C.; Kuchroo, V.K. TIM3 comes of age as an inhibitory receptor. Nat. Rev. Immunol. 2020, 20, 173–185. [Google Scholar] [CrossRef]
- Chiba, S.; Baghdadi, M.; Akiba, H.; Yoshiyama, H.; Kinoshita, I.; Dosaka-Akita, H.; Fujioka, Y.; Ohba, Y.; Gorman, J.V.; Colgan, J.D.; et al. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 2012, 13, 832–842. [Google Scholar] [CrossRef]
- Zhang, Y.; Cai, P.; Li, L.; Shi, L.; Chang, P.; Liang, T.; Yang, Q.; Liu, Y.; Wang, L.; Hu, L. Co-expression of TIM-3 and CEACAM1 promotes T cell exhaustion in colorectal cancer patients. Int. Immunopharmacol. 2017, 43, 210–218. [Google Scholar] [CrossRef]
- Xu, B.; Yuan, L.; Gao, Q.; Yuan, P.; Zhao, P.; Yuan, H.; Fan, H.; Li, T.; Qin, P.; Han, L.; et al. Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer. Oncotarget 2015, 6, 20592–20603. [Google Scholar] [CrossRef] [Green Version]
- Sasidharan Nair, V.; Toor, S.M.; Taha, R.Z.; Ahmed, A.A.; Kurer, M.A.; Murshed, K.; Soofi, M.E.; Ouararhni, K.; Alajez, N.M.; Abu Nada, M. Transcriptomic profiling of tumor-infiltrating CD4+TIM-3+ T cells reveals their suppressive, exhausted, and metastatic characteristics in colorectal cancer patients. Vaccines 2020, 8, 71. [Google Scholar] [CrossRef] [Green Version]
- Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer 2013, 13, 714–726. [Google Scholar] [CrossRef]
- Van der Bij, G.J.; Oosterling, S.J.; Beelen, R.H.J.; Meijer, S.; Coffey, J.C.; van Egmond, M. The Perioperative Period is an Underutilized Window of Therapeutic Opportunity in Patients with Colorectal Cancer. Ann. Surg. 2009, 249, 727–734. [Google Scholar] [CrossRef] [Green Version]
- Emambux, S.; Tachon, G.; Junca, A.; Tougeron, D. Results and challenges of immune checkpoint inhibitors in colorectal cancer. Expert Opin. Biol. Ther. 2018, 18, 561–573. [Google Scholar] [CrossRef]
- Gotwals, P.; Cameron, S.; Cipolletta, D.; Cremasco, V.; Crystal, A.; Hewes, B.; Mueller, B.; Quaratino, S.; Sabatos-Peyton, C.; Petruzzelli, L. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer 2017, 17, 286–301. [Google Scholar] [CrossRef]
- Hargadon, K.M.; Johnson, C.E.; Williams, C.J. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 2018, 62, 29–39. [Google Scholar] [CrossRef]
- Xu, J.; Xu, L.; Wang, C.; Yang, R.; Zhuang, Q.; Han, X.; Dong, Z.; Zhu, W.; Peng, R.; Liu, Z. Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer. ACS Nano 2017, 11, 4463–4474. [Google Scholar] [CrossRef]
- Morse, M.A.; Hochster, H.; Benson, A. Perspectives on Treatment of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitor Therapy. Oncologist 2020, 25, 33–45. [Google Scholar] [CrossRef] [Green Version]
- Kirkwood, J.M.; Butterfield, L.H.; Tarhini, A.A.; Zarour, H.; Kalinski, P.; Ferrone, S. Immunotherapy of cancer in 2012. CA Cancer J. Clin. 2012, 62, 309–335. [Google Scholar] [CrossRef]
- Saltz, L.B. Looking ahead: What will change in colorectal cancer treatment? Gastrointest. Cancer Res. 2009, 3, S16. [Google Scholar]
- Lynch, D.; Murphy, A. The emerging role of immunotherapy in colorectal cancer. Ann. Transl. Med. 2016, 4, 305. [Google Scholar] [CrossRef] [Green Version]
- Kamatham, S.; Shahjehan, F.; Kasi, P.M. Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer: Current Status, Recent Advances, and Future Directions. Curr. Color. Cancer Rep. 2019, 15, 112–121. [Google Scholar] [CrossRef] [Green Version]
- Zhao, Y.; Yang, W.; Huang, Y.; Cui, R.; Li, X.; Li, B. Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy. Cell. Physiol. Biochem. 2018, 47, 721–734. [Google Scholar] [CrossRef]
- Sanghavi, K.; Zhang, J.; Zhao, X.; Feng, Y.; Statkevich, P.; Sheng, J.; Roy, A.; Vezina, H.E. Population Pharmacokinetics of Ipilimumab in Combination With Nivolumab in Patients With Advanced Solid Tumors. CPT Pharmacomet. Syst. Pharmacol. 2020, 9, 29–39. [Google Scholar] [CrossRef]
- 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.; et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer. J. Clin. 2018, 36, 773–779. [Google Scholar] [CrossRef]
- Camacho, L.H. Novel therapies targeting the immune system: CTLA4 blockade with tremelimumab (CP-675,206), a fully human monoclonal antibody. Expert Opin. Investig. Drugs 2008, 17, 371–385. [Google Scholar] [CrossRef]
- Chung, K.Y.; Gore, I.; Fong, L.; Venook, A.; Beck, S.B.; Dorazio, P.; Criscitiello, P.J.; Healey, D.I.; Huang, B.; Gomez-Navarro, J. 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, 3485–3490. [Google Scholar] [CrossRef]
- Sangro, B.; Gomez-Martin, C.; de la Mata, M.; Iñarrairaegui, M.; Garralda, E.; Barrera, P.; Riezu-Boj, J.I.; Larrea, E.; Alfaro, C.; Sarobe, P. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 2013, 59, 81–88. [Google Scholar] [CrossRef]
- Duffy, A.G.; Ulahannan, S.V.; Makorova-Rusher, O.; Rahma, O.; Wedemeyer, H.; Pratt, D.; Davis, J.L.; Hughes, M.S.; Heller, T.; ElGindi, M.; et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 2017, 66, 545–551. [Google Scholar] [CrossRef] [Green Version]
- 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. 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, 831–838. [Google Scholar] [CrossRef]
- Makuku, R.; Khalili, N.; Razi, S.; Keshavarz-Fathi, M.; Rezaei, N. Current and Future Perspectives of PD-1/PDL-1 Blockade in Cancer Immunotherapy. J. Immunol. Res. 2021, 2021, 6661406. [Google Scholar] [CrossRef]
- Wu, X.; Zhang, H.; Xing, Q.; Cui, J.; Li, J.; Li, Y.; Tan, Y.; Wang, S. PD-1+ CD8+ T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients. Br. J. Cancer 2014, 111, 1391–1399. [Google Scholar] [CrossRef] [Green Version]
- Hahn, A.W.; Gill, D.M.; Agarwal, N.; Maughan, B.L. PD-1 checkpoint inhibition: Toxicities and management. Urol. Oncol. 2017, 35, 701–707. [Google Scholar] [CrossRef]
- Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H., Jr.; Lao, C.D. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015, 16, 375–384. [Google Scholar] [CrossRef]
- Overman, M.J.; McDermott, R.; Leach, J.L.; Lonardi, S.; Lenz, H.-J.; Morse, M.A.; Desai, J.; Hill, A.; Axelson, M.; Moss, R.A.; 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, 1182–1191. [Google Scholar] [CrossRef]
- Jácome, A.A.; Eng, C. Role of immune checkpoint inhibitors in the treatment of colorectal cancer: Focus on Nivolumab. Expert Opin. Biol. Ther. 2019, 19, 1247–1263. [Google Scholar] [CrossRef]
- Marcus, L.; Lemery, S.J.; Keegan, P.; Pazdur, R. FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin. Cancer Res. 2019, 25, 3753–3758. [Google Scholar] [CrossRef] [Green Version]
- Scapin, G.; Yang, X.; Prosise, W.W.; McCoy, M.; Reichert, P.; Johnston, J.M.; Kashi, R.S.; Strickland, C. Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat. Struct. Mol. Biol. 2015, 22, 953–958. [Google Scholar] [CrossRef]
- Kawazoe, A.; Kuboki, Y.; Shinozaki, E.; Hara, H.; Nishina, T.; Komatsu, Y.; Yuki, S.; Wakabayashi, M.; Nomura, S.; Sato, A.; et al. Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial). Clin. Cancer Res. 2020, 26, 5887–5894. [Google Scholar] [CrossRef]
- O’Neil, B.H.; Wallmark, J.M.; Lorente, D.; Elez, E.; Raimbourg, J.; Gomez-Roca, C.; Ejadi, S.; Piha-Paul, S.A.; Stein, M.N.; Razak, A.R.A.; et al. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS ONE 2017, 12, e0189848. [Google Scholar] [CrossRef] [Green Version]
- Morse, M.A.; Overman, M.J.; Hartman, L.; Khoukaz, T.; Brutcher, E.; Lenz, H.J.; Atasoy, A.; Shangguan, T.; Zhao, H.; 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, 1453–1461. [Google Scholar] [CrossRef] [Green Version]
- Balar, A.V.; Galsky, M.D.; Rosenberg, J.E.; Powles, T.; Petrylak, D.P.; Bellmunt, J.; Loriot, Y.; Necchi, A.; Hoffman-Censits, J.; Perez-Gracia, J.L.; et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 2017, 389, 67–76. [Google Scholar] [CrossRef] [Green Version]
- Carretero-González, A.; Lora, D.; Ghanem, I.; Zugazagoitia, J.; Castellano, D.; Sepúlveda, J.M.; López-Martin, J.A.; Paz-Ares, L.; De Velasco, G. Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: A meta-analysis of randomized clinical trials. Oncotarget 2018, 9, 8706–8715. [Google Scholar] [CrossRef] [Green Version]
- Horn, L.; Mansfield, A.S.; Szczęsna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2220–2229. [Google Scholar] [CrossRef]
- Hochster, H.S.; Bendell, J.C.; Cleary, J.M.; Foster, P.; Zhang, W.; He, X.; Hernandez, G.; Iizuka, K.; Eckhardt, S.G. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). J. Clin. Oncol. 2017, 35, 673. [Google Scholar] [CrossRef]
- Tan, S.; Liu, K.; Chai, Y.; Zhang, C.W.-H.; Gao, S.; Gao, G.F.; Qi, J. Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab. Protein Cell 2018, 9, 135–139. [Google Scholar] [CrossRef]
- Segal, N.H.; Wainberg, Z.A.; Overman, M.J.; Ascierto, P.A.; Arkenau, H.-T.; Butler, M.O.; Eder, J.P.; Keilholz, U.; Kim, D.-W.; Cunningham, D.; et al. Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability–high (MSI-H) tumors. J. Clin. Oncol. 2019, 37, 670. [Google Scholar] [CrossRef]
- Heery, C.R.; O’Sullivan-Coyne, G.; Madan, R.A.; Cordes, L.; Rajan, A.; Rauckhorst, M.; Lamping, E.; Oyelakin, I.; Marté, J.L.; Lepone, L.M.; et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): A phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017, 18, 587–598. [Google Scholar] [CrossRef]
- Wang, H.; Yao, H.; Li, C.; Liang, L.; Zhang, Y.; Shi, H.; Zhou, C.; Chen, Y.; Fang, J.-Y.; Xu, J. PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation. Oncoimmunology 2017, 6, e1327494. [Google Scholar] [CrossRef] [Green Version]
- Guo, P.-D.; Sun, Z.-W.; Lai, H.-J.; Yang, J.; Wu, P.-P.; Guo, Y.-D.; Sun, J. Clinicopathological analysis of PD-L2 expression in colorectal cancer. OncoTargets Ther. 2018, 11, 7635–7642. [Google Scholar] [CrossRef] [Green Version]
- Mishra, A.K.; Kadoishi, T.; Wang, X.; Driver, E.; Chen, Z.; Wang, X.-J.; Wang, J.H. Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors. Oncotarget 2016, 7, 81341–81356. [Google Scholar] [CrossRef] [Green Version]
- Ruffo, E.; Wu, R.C.; Bruno, T.C.; Workman, C.J.; Vignali, D.A. Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor. Semin. Immunol. 2019, 42, 101305. [Google Scholar] [CrossRef]
- Rohatgi, A.; Massa, R.C.; Gooding, W.E.; Bruno, T.C.; Vignali, D.; Kirkwood, J.M. A phase II study of anti-PD1 monoclonal antibody (Nivolumab) administered in combination with anti-LAG3 monoclonal antibody (Relatlimab) in patients with metastatic melanoma naive to prior immunotherapy in the metastatic setting. J. Clin. Oncol. 2020, 38, TPS10085. [Google Scholar] [CrossRef]
- Hong, D.S.; Schoffski, P.; Calvo, A.; Sarantopoulos, J.; De Olza, M.O.; Carvajal, R.D.; Prawira, A.; Kyi, C.; Esaki, T.; Akerley, W.L.; et al. Phase I/II study of LAG525 ± spartalizumab (PDR001) in patients (pts) with advanced malignancies. J. Clin. Oncol. 2018, 36, 3012. [Google Scholar] [CrossRef]
- Uboha, N.V.; Milhem, M.M.; Kovacs, C.; Amin, A.; Magley, A.; Das Purkayastha, D.; Piha-Paul, S.A. Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies. J. Clin. Oncol. 2019, 37, 2553. [Google Scholar] [CrossRef]
- Gregory, G.P.; Zinzani, P.L.; Palcza, J.; Healy, J.A.; Orlowski, R.J.; Nahar, A.; Armand, P. Abstract CT106: Anti-LAG-3 antibody MK-4280 in combination with pembrolizumab for the treatment of hematologic malignancies: A phase I/II study. In Proceedings of the AACR Annual Meeting 2019, Atlanta, GA, USA, 29 March–3 April 2019. [Google Scholar]
- Yu, X.; Huang, X.; Chen, X.; Liu, J.; Wu, C.; Pu, Q.; Wang, Y.; Kang, X.; Zhou, L. Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy. mAbs 2019, 11, 1139–1148. [Google Scholar] [CrossRef]
- Sabatos-Peyton, C.A.; Nevin, J.; Brock, A.; Venable, J.D.; Tan, D.J.; Kassam, N.; Xu, F.; Taraszka, J.; Wesemann, L.; Pertel, T.; et al. Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy. Oncoimmunology 2018, 7, e1385690. [Google Scholar] [CrossRef] [Green Version]
- Acharya, N.; Sabatos-Peyton, C.; Anderson, A.C. Tim-3 finds its place in the cancer immunotherapy landscape. J. Immunother. Cancer 2020, 8, e000911. [Google Scholar] [CrossRef]
- Curigliano, G.; Gelderblom, H.; Mach, N.; Doi, T.; Tai, W.M.D.; Forde, P.; Sarantopoulos, J.; Bedard, P.L.; Lin, C.-C.; Hodi, S. Abstract CT183: Phase (Ph) I/II study of MBG453±spartalizumab (PDR001) in patients (pts) with advanced malignancies. In Proceedings of the AACR Annual Meeting 2019, Atlanta, GA, USA, 29 March–3 April 2019. [Google Scholar]
- Stein, A.; Folprecht, G. Immunotherapy of Colon Cancer. Oncol. Res. Treat. 2018, 41, 282–285. [Google Scholar] [CrossRef]
- Fiegle, E.; Doleschel, D.; Koletnik, S.; Rix, A.; Weiskirchen, R.; Borkham-Kamphorst, E.; Kiessling, F.; Lederle, W. Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer. Neoplasia 2019, 21, 932–944. [Google Scholar] [CrossRef]
- Koyama, S.; Akbay, E.A.; Li, Y.Y.; Herter-Sprie, G.S.; Buczkowski, K.A.; Richards, W.G.; Gandhi, L.; Redig, A.J.; Rodig, S.J.; Asahina, H.; et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 2016, 7, 10501. [Google Scholar] [CrossRef]
- Xiao, Y.; Freeman, G.J. The Microsatellite Instable Subset of Colorectal Cancer Is a Particularly Good Candidate for Checkpoint Blockade Immunotherapy. Cancer Discov. 2015, 5, 16–18. [Google Scholar] [CrossRef] [Green Version]
- Armand, P.; Zinzani, P.L.L.; Palcza, J.; Healy, J.A.; Nahar, A.; Marinello, P.; Gregory, G.P. Phase 1-2 Study of Pembrolizumab Combined with the Anti-LAG-3 Antibody MK-4280 for the Treatment of Hematologic Malignancies. Blood 2019, 134, 1548. [Google Scholar] [CrossRef]
- Harding, J.J.; Patnaik, A.; Moreno, V.; Stein, M.; Jankowska, A.M.; de Mendizabal, N.V.; Liu, Z.T.; Koneru, M.; Calvo, E. A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers. J. Clin. Oncol. 2019, 37, 12. [Google Scholar] [CrossRef]
- Taefehshokr, N.; Baradaran, B.; Baghbanzadeh, A.; Taefehshokr, S. Promising approaches in cancer immunotherapy. Immunobiology 2020, 225, 151875. [Google Scholar] [CrossRef]
- Greil, R.; Hutterer, E.; Hartmann, T.N.; Pleyer, L. Reactivation of dormant anti-tumor immunity–a clinical perspective of therapeutic immune checkpoint modulation. Cell Commun. Signal. 2017, 15, 1–16. [Google Scholar] [CrossRef] [Green Version]
- Li, B.; VanRoey, M.; Wang, C.; Chen, T.-H.T.; Korman, A.; Jooss, K. Anti–Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors. Clin. Cancer Res. 2009, 15, 1623–1634. [Google Scholar] [CrossRef] [Green Version]
- Tian, H.; Shi, G.; Wang, Q.; Li, Y.; Yang, Q.; Li, C.; Yang, G.; Wu, M.; Xie, Q.; Zhang, S.; et al. A novel cancer vaccine with the ability to simultaneously produce anti-PD-1 antibody and GM-CSF in cancer cells and enhance Th1-biased antitumor immunity. Signal Transduct. Target. Ther. 2016, 1, 16025. [Google Scholar] [CrossRef] [Green Version]
- Yin, L.; Zhao, C.; Han, J.; Li, Z.; Zhen, Y.; Xiao, R.; Xu, Z.; Sun, Y. Antitumor effects of oncolytic herpes simplex virus type 2 against colorectal cancer in vitro and in vivo. Ther. Clin. Risk Manag. 2017, 13, 117–130. [Google Scholar] [CrossRef] [Green Version]
- Rajani, K.; Parrish, C.; Kottke, T.; Thompson, J.; Zaidi, S.; Ilett, E.; Shim, K.G.; Diaz, R.-M.; Pandha, H.; Harrington, K.; et al. Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses. Mol. Ther. 2016, 24, 166–174. [Google Scholar] [CrossRef] [Green Version]
- Ribas, A.; Dummer, R.; Puzanov, I.; VanderWalde, A.; Andtbacka, R.H.; Michielin, O.; Olszanski, A.J.; Malvehy, J.; Cebon, J.; Fernandez, E.; et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell 2017, 170, 1109–1119.e10. [Google Scholar] [CrossRef] [Green Version]
- Kuryk, L.; Møller, A.-S.W.; Jaderberg, M. Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model. Oncoimmunology 2019, 8, e1532763. [Google Scholar] [CrossRef]
- Sun, L.; Funchain, P.; Song, J.M.; Rayman, P.; Tannenbaum, C.; Ko, J.; McNamara, M.; Diaz-Montero, C.M.; Gastman, B. Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: A case series. J. Immunother. Cancer 2018, 6, 36. [Google Scholar] [CrossRef]
- Sun, Y.; Wang, S.; Yang, H.; Wu, J.; Li, S.; Qiao, G.; Wang, S.; Wang, X.; Zhou, X.; Osada, T.; et al. Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth. Immunotherapy 2019, 11, 953–966. [Google Scholar] [CrossRef]
- Yoo, S.Y.; Badrinath, N.; Jeong, S.-N.; Woo, H.Y.; Heo, J. Overcoming Tumor Resistance to Oncolyticvaccinia Virus with Anti-PD-1-Based Combination Therapy by Inducing Antitumor Immunity in the Tumor Microenvironment. Vaccines 2020, 8, 321. [Google Scholar] [CrossRef]
- Newick, K.; O’Brien, S.; Moon, E.; Albelda, S.M. CAR T Cell Therapy for Solid Tumors. Annu. Rev. Med. 2017, 68, 139–152. [Google Scholar] [CrossRef]
- John, L.B.; Kershaw, M.H.; Darcy, P.K. Blockade of PD-1 immunosuppression boosts CAR T-cell therapy. Oncoimmunology 2013, 2, e26286. [Google Scholar] [CrossRef]
- Chen, N.; Morello, A.; Tano, Z.; Adusumilli, P.S. CAR T-cell intrinsic PD-1 checkpoint blockade: A two-in-one approach for solid tumor immunotherapy. Oncoimmunology 2017, 6, e1273302. [Google Scholar] [CrossRef] [Green Version]
- Gibney, G.T.; Hamid, O.; Lutzky, J.; Olszanski, A.J.; Mitchell, T.C.; Gajewski, T.F.; Chmielowski, B.; Hanks, B.A.; Zhao, Y.; Newton, R.C. Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. J. Immunother. Cancer 2019, 7, 1–13. [Google Scholar] [CrossRef] [Green Version]
- Ahn, M.-J.; Sun, J.-M.; Lee, S.-H.; Ahn, J.S.; Park, K. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert Opin. Drug Saf. 2017, 16, 465–469. [Google Scholar] [CrossRef]
- Jia, Y.; Li, X.; Jiang, T.; Zhao, S.; Zhao, C.; Zhang, L.; Liu, X.; Shi, J.; Qiao, M.; Luo, J.; et al. EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination therapies. Int. J. Cancer 2019, 145, 1432–1444. [Google Scholar] [CrossRef]
- Li, Y.; Du, Y.; Liang, X.; Sun, T.; Xue, H.; Tian, J.; Jin, Z. EGFR-targeted liposomal nanohybrid cerasomes: Theranostic function and immune checkpoint inhibition in a mouse model of colorectal cancer. Nanoscale 2018, 10, 16738–16749. [Google Scholar] [CrossRef]
- Fukumura, D.; Kloepper, J.; Amoozgar, Z.; Duda, D.G.; Jain, R.K. Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges. Nat. Rev. Clin. Oncol. 2018, 15, 325–340. [Google Scholar] [CrossRef]
- Wrobel, P.; Ahmed, S. Current status of immunotherapy in metastatic colorectal cancer. Int. J. Color. Dis. 2019, 34, 13–25. [Google Scholar] [CrossRef]
- Carter, T.; Shaw, H.; Cohn-Brown, D.; Chester, K.; Mulholland, P. Ipilimumab and Bevacizumab in Glioblastoma. Clin. Oncol. 2016, 28, 622–626. [Google Scholar] [CrossRef] [Green Version]
- Song, M. Recent developments in small molecule therapies for renal cell carcinoma. Eur. J. Med. Chem. 2017, 142, 383–392. [Google Scholar] [CrossRef]
- Antoniotti, C.; Borelli, B.; Rossini, D.; Pietrantonio, F.; Morano, F.; Salvatore, L.; Lonardi, S.; Marmorino, F.; Tamberi, S.; Corallo, S.; et al. AtezoTRIBE: A randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer. BMC Cancer 2020, 20, 683. [Google Scholar] [CrossRef]
- Fallarino, F.; Grohmann, U.; Vacca, C.; Bianchi, R.; Orabona, C.; Spreca, A.; Fioretti, M.C.; Puccetti, P. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002, 9, 1069–1077. [Google Scholar] [CrossRef]
- Sharma, M.D.; Baban, B.; Chandler, P.; Hou, D.-Y.; Singh, N.; Yagita, H.; Azuma, M.; Blazar, B.R.; Mellor, A.L.; Munn, D.H. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Investig. 2007, 117, 2570–2582. [Google Scholar] [CrossRef] [Green Version]
- Brown, Z.J.; Yu, S.J.; Heinrich, B.; Ma, C.; Fu, Q.; Sandhu, M.; Agdashian, D.; Zhang, Q.; Korangy, F.; Greten, T.F. Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol. Immunother. 2018, 67, 1305–1315. [Google Scholar] [CrossRef]
- Dubovsky, J.A.; Beckwith, K.A.; Natarajan, G.; Woyach, J.A.; Jaglowski, S.; Zhong, Y.; Hessler, J.D.; Liu, T.-M.; Chang, B.Y.; Larkin, K.M.; et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013, 122, 2539–2549. [Google Scholar] [CrossRef] [Green Version]
- Sagiv-Barfi, I.; Kohrt, H.E.K.; Czerwinski, D.K.; Ng, P.P.; Chang, B.Y.; Levy, R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc. Natl. Acad. Sci. USA 2015, 112, E966–E972. [Google Scholar] [CrossRef] [Green Version]
- Yan, Y.; Kumar, A.B.; Finnes, H.; Markovic, S.N.; Park, S.; Dronca, R.S.; Dong, H. Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy. Front. Immunol. 2018, 9, 1739. [Google Scholar] [CrossRef] [Green Version]
- Lhuillier, C.; Vanpouille-Box, C.; Galluzzi, L.; Formenti, S.C.; Demaria, S. Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers. Semin. Cancer Biol. 2018, 52, 125–134. [Google Scholar] [CrossRef]
- Herrera, F.G.; Bourhis, J.; Coukos, G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J. Clin. 2017, 67, 65–85. [Google Scholar] [CrossRef]
- Hwang, W.L.; Pike, L.R.G.; Royce, T.J.; Mahal, B.A.; Loeffler, J.S. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat. Rev. Clin. Oncol. 2018, 15, 477–494. [Google Scholar] [CrossRef]
- Sha, C.; Lehrer, E.J.; Hwang, C.; Trifiletti, D.M.; Mackley, H.B.; Drabick, J.J.; Zaorsky, N.G. Toxicity in combination immune checkpoint inhibitor and radiation therapy: A systematic review and meta-analysis. Radiother. Oncol. 2020, 151, 141–148. [Google Scholar] [CrossRef]
- Dovedi, S.J.; Cheadle, E.J.; Popple, A.L.; Poon, E.; Morrow, M.; Stewart, R.; Yusko, E.C.; Sanders, C.M.; Vignali, M.; Emerson, R.O.; et al. Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade. Clin. Cancer Res. 2017, 23, 5514–5526. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.; Schoenhals, J.E.; Li, A.; Valdecanas, D.R.; Ye, H.; Zhang, F.; Tang, C.; Tang, M.; Liu, C.-G.; Liu, X.; et al. Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy. Cancer Res. 2017, 77, 839–850. [Google Scholar] [CrossRef] [Green Version]
- Grimaldi, A.M.; Simeone, E.; Giannarelli, D.; Muto, P.; Falivene, S.; Borzillo, V.; Giugliano, F.M.; Sandomenico, F.; Petrillo, A.; Curvietto, M.; et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 2014, 3, e28780. [Google Scholar] [CrossRef]
- Schmidberger, H.; Rapp, M.; Ebersberger, A.; Hey-Koch, S.; Loquai, C.; Grabbe, S.; Mayer, A. Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: Sequence matters. Strahlenther. Onkol. 2018, 194, 1144–1151. [Google Scholar] [CrossRef] [Green Version]
- Asadzadeh, Z.; Safarzadeh, E.; Safaei, S.; Baradaran, A.; Mohammadi, A.; Hajiasgharzadeh, K.; Derakhshani, A.; Argentiero, A.; Silvestris, N.; Baradaran, B. Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death. Cancers 2020, 12, 1047. [Google Scholar] [CrossRef] [Green Version]
- Zitvogel, L.; Apetoh, L.; Ghiringhelli, F.; Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 2008, 8, 59–73. [Google Scholar] [CrossRef]
- Pfirschke, C.; Engblom, C.; Rickelt, S.; Cortez-Retamozo, V.; Garris, C.; Pucci, F.; Yamazaki, T.; Poirier-Colame, V.; Newton, A.; Redouane, Y.; et al. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 2016, 44, 343–354. [Google Scholar] [CrossRef] [Green Version]
- Ghiringhelli, F.; Menard, C.; Puig, P.E.; Ladoire, S.; Roux, S.; Martin, F.; Solary, E.; Le Cesne, A.; Zitvogel, L.; Chauffert, B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 2007, 56, 641–648. [Google Scholar] [CrossRef]
- Alizadeh, D.; Larmonier, N. Chemotherapeutic Targeting of Cancer-Induced Immunosuppressive Cells. Cancer Res. 2014, 74, 2663–2668. [Google Scholar] [CrossRef] [Green Version]
- Dosset, M.; Vargas, T.R.; Lagrange, A.; Boidot, R.; Vegran, F.; Roussey, A.; Chalmin, F.; Dondaine, L.; Paul, C.; Marie-Joseph, E.L.; et al. PD-1/PD-L1 pathway: An adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. OncoImmunology 2018, 7, e1433981. [Google Scholar] [CrossRef] [Green Version]
- Yu, G.; Wu, Y.; Wang, W.; Xu, J.; Lv, X.; Cao, X.; Wan, T. Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell. Mol. Immunol. 2019, 16, 401–409. [Google Scholar] [CrossRef]
- Leonetti, A.; Wever, B.; Mazzaschi, G.; Assaraf, Y.G.; Rolfo, C.; Quaini, F.; Tiseo, M.; Giovannetti, E. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist. Updates 2019, 46, 100644. [Google Scholar] [CrossRef]
- Fumet, J.-D.; Isambert, N.; Hervieu, A.; Zanetta, S.; Guion, J.-F.; Hennequin, A.; Rederstorff, E.; Bertaut, A.; Ghiringhelli, F. Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736)(anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer. ESMO Open 2018, 3, e000375. [Google Scholar] [CrossRef] [Green Version]
- Jure-Kunkel, M.; Masters, G.; Girit, E.; Dito, G.; Lee, F.; Hunt, J.T.; Humphrey, R. Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models. Cancer Immunol. Immunother. 2013, 62, 1533–1545. [Google Scholar] [CrossRef] [Green Version]
- Guan, Y.; Kraus, S.G.; Quaney, M.J.; Daniels, M.A.; Mitchem, J.B.; Teixeiro, E. FOLFOX Chemotherapy Ameliorates CD8 T Lymphocyte Exhaustion and Enhances Checkpoint Blockade Efficacy in Colorectal Cancer. Front. Oncol. 2020, 10, 586. [Google Scholar] [CrossRef]
- Wang, W.; Wu, L.; Zhang, J.; Wu, H.; Han, E.; Guo, Q. Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model. Biochem. Biophys. Res. Commun. 2017, 487, 1–7. [Google Scholar] [CrossRef]
- Black, M.; Barsoum, I.B.; Truesdell, P.; Cotechini, T.; Macdonald-Goodfellow, S.K.; Petroff, M.; Siemens, D.R.; Koti, M.; Craig, A.W.; Graham, C.H. Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget 2016, 7, 10557–10567. [Google Scholar] [CrossRef] [Green Version]
- Yarchoan, M.; Huang, C.Y.; Zhu, Q.; Ferguson, A.K.; Durham, J.N.; Anders, R.A.; Thompson, E.D.; Rozich, N.S.; Thomas, D.L.; Nauroth, J.M.; et al. A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer. Cancer Med. 2020, 9, 1485–1494. [Google Scholar] [CrossRef]
- Schafflick, D.; Xu, C.A.; Hartlehnert, M.; Cole, M.; Schulte-Mecklenbeck, A.; Lautwein, T.; Wolbert, J.; Heming, M.; Meuth, S.G.; Kuhlmann, T.; et al. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat. Commun. 2020, 11, 247. [Google Scholar] [CrossRef] [Green Version]
- Eng, C.; Kim, T.W.; Bendell, J.; Argilés, G.; Tebbutt, N.C.; Di Bartolomeo, M.; Falcone, A.; Fakih, M.; Kozloff, M.; Segal, N.H.; 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, 849–861. [Google Scholar] [CrossRef]
- Deming, D.A.; Emmerich, P.; Turk, A.A.; Lubner, S.J.; Uboha, N.V.; LoConte, N.K.; Mulkerin, D.; Kim, D.H.; Matkowskyj, K.A.; Weber, S.M.; et al. Pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver oligometastatic MSS/MMR proficient colorectal cancer (CRC). J. Clin. Oncol. 2020, 38, 4046. [Google Scholar] [CrossRef]
- Myers, G. Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Brief Review. Curr. Oncol. 2018, 25, 342–347. [Google Scholar] [CrossRef] [Green Version]
- Zhang, B.; Wu, Q.; Zhou, Y.L.; Guo, X.; Ge, J.; Fu, J. Immune-related adverse events from combination immunotherapy in cancer patients: A comprehensive meta-analysis of randomized controlled trials. Int. Immunopharmacol. 2018, 63, 292–298. [Google Scholar] [CrossRef]
- Wang, D.Y.; Salem, J.-E.; Cohen, J.V.; Chandra, S.; Menzer, C.; Ye, F.; Zhao, S.; Das, S.; Beckermann, K.E.; Ha, L. Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta-analysis. JAMA Oncol. 2018, 4, 1721–1728. [Google Scholar] [CrossRef] [Green Version]
- Friedman, C.F.; Proverbs-Singh, T.A.; Postow, M.A. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: A review. JAMA Oncol. 2016, 2, 1346–1353. [Google Scholar] [CrossRef]
- Logan, I.T.; Zaman, S.; Hussein, L.; Perrett, C.M. Combination Therapy of Ipilimumab and Nivolumab-associated Toxic Epidermal Necrolysis (TEN) in a Patient With Metastatic Melanoma: A Case Report and Literature Review. J. Immunother. 2020, 43, 89–92. [Google Scholar] [CrossRef]
- Sutaria, R.; Patel, P.; Danve, A. Autoimmune myositis and myasthenia gravis resulting from a combination therapy with Nivolumab and ipilimumab for metastatic melanoma. Eur. J. Rheumatol. 2019, 6, 153–154. [Google Scholar] [CrossRef]
Target | mAbs | Patients | Phase | Trial | Ref |
---|---|---|---|---|---|
CTLA-4 | Tremelimumab | mCRC | II | A study that showed no significant activity of Tremelimumab as monotherapy in refractory metastatic colorectal cancer patients. | [117] |
PD-1 | Nivolumab | dMMR/MSI-H mCRC | II | A study evaluating Nivolumab in colon cancer was associated with durable responses in patients with previous treatments. | [125] |
PD-1 | Pembrolizumab | MSI-H/MSS mCRC | I/II | An assessment of Pembrolizumab with napabucasin that showed antitumor effects with acceptable toxicities in mCRC patients. | [129] |
PD-1 | Pembrolizumab | MMRp CRC | II | A study to investigate efficacy of Pembrolizumab plus with GVAX/Cy showed no efficacy in mismatch repair proficient CRC. | [207] |
Anti-PD-L1 | Durvalumab | MSI-H CRC | II | An evaluation of the efficacy and safety of Durvalumab demonstrated a well-tolerable response in MSI-H CRC patients. | [137] |
Combination of Immune Checkpoint Inhibitors | |||||
CTLA-4 and PD-1 | Ipilimumab and Nivolumab | dMMR/MSI-H mCRC | - | An assessment of Ipilimumab in combination with Nivolumab, which suggested of significant antitumor activity in dMMR/MSI-H mCRC. | [115] |
CTLA-4 and PD-L1 | Tremelimumab and Durvalumab | refractory CRC | II | An assessment of the efficacy of Tremelimumab and Durvalumab that showed enhanced overall survival (OS) in patients with advanced refractory CRC. | [208] |
Combination ICIs Plus Other Immunotherapy | |||||
PD-L1 | Atezolizumab and cobimetinib | mCRC | III | An assessment of the antitumor effect and safety of combined Atezolizumab with cobimetinib and Atezolizumab monotherapy vs. regorafenib in patients with mCRC. | [209] |
PD-L1 | Atezolizumab and FOLFOXIRI/bevacizumab | mCRC | II | An evaluation of the efficacy of the combination of Atezolizumab with chemotherapy plus Bevacizumab in mCRC patients. | [179] |
Combination ICIs Plus Radiotherapy | |||||
PD-1 | Pembrolizumab and Radiotherapy | Liver mCRC | Ib | An evaluation of the efficacy of the combination of stereotactic body radiotherapy for resectable liver oligometastatic in MSS/MMR proficient CRC. | [210] |
Combination ICIs Plus Chemotherapy | |||||
PD-L1 | Atezolizumab and FOLFOXIRI/bevacizumab | mCRC | II | An evaluation of the effect of the combination of Atezolizumab with chemotherapy plus Bevacizumab in mCRC. | [179] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Makaremi, S.; Asadzadeh, Z.; Hemmat, N.; Baghbanzadeh, A.; Sgambato, A.; Ghorbaninezhad, F.; Safarpour, H.; Argentiero, A.; Brunetti, O.; Bernardini, R.; et al. Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects. Biomedicines 2021, 9, 1075. https://doi.org/10.3390/biomedicines9091075
Makaremi S, Asadzadeh Z, Hemmat N, Baghbanzadeh A, Sgambato A, Ghorbaninezhad F, Safarpour H, Argentiero A, Brunetti O, Bernardini R, et al. Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects. Biomedicines. 2021; 9(9):1075. https://doi.org/10.3390/biomedicines9091075
Chicago/Turabian StyleMakaremi, Shima, Zahra Asadzadeh, Nima Hemmat, Amir Baghbanzadeh, Alessandro Sgambato, Farid Ghorbaninezhad, Hossein Safarpour, Antonella Argentiero, Oronzo Brunetti, Renato Bernardini, and et al. 2021. "Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects" Biomedicines 9, no. 9: 1075. https://doi.org/10.3390/biomedicines9091075