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Review

Immune checkpoint inhibitors: maximizing benefit whilst minimizing toxicity

ORCID Icon, &
Pages 673-683 | Received 25 Oct 2022, Accepted 15 May 2023, Published online: 22 May 2023

References

  • Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1(9):793–801. DOI:10.1016/S1074-7613(94)80021-9
  • Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201–1217. DOI:10.1084/jem.20112741
  • Vaddepally RK, Kharel P, Pandey R, et al. Review of indications of FDA-Approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel). 2020;12(3):738. DOI:10.3390/cancers12030738
  • Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–895. DOI:10.1084/jem.20051776
  • Janakiram M, Shah UA, Liu W, et al. The third group of the B7- CD 28 immune checkpoint family: hHLA 2, TMIGD 2, B7x, and B7-H3. Immunol Rev. 2017;276(1):26–39. DOI:10.1111/imr.12521
  • Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–2532. DOI:10.1056/NEJMoa1503093
  • Weber JS, D’Angelo SP, Minor D, et al. 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(4):375–384. DOI:10.1016/S1470-2045(15)70076-8
  • Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341–351. DOI:10.1056/NEJMoa1805131
  • Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–Positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833. DOI:10.1056/NEJMoa1606774
  • Mok TSK, Wu Y-L, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–1830. DOI:10.1016/S0140-6736(18)32409-7
  • Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med. 2015;373(2):123–135. DOI:10.1056/NEJMoa1504627
  • Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397(10274):592–604. DOI:10.1016/S0140-6736(21)00228-2
  • Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–2350. DOI:10.1056/NEJMoa1809697
  • Halmos B, Burke T, Kalyvas C, et al. Pembrolizumab+chemotherapy versus atezolizumab+chemotherapy±bevacizumab for the first-line treatment of non-squamous NSCLC: a matching-adjusted indirect comparison. Lung Cancer. 2021;155:175–182.
  • Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–1846. DOI:10.1016/S0140-6736(16)00587-0
  • Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–322. DOI:10.1016/S1470-2045(17)30065-7
  • Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102–2114. DOI:10.1056/NEJMoa2034442
  • Necchi A, Joseph RW, Loriot Y, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017;28(12):3044–3050. DOI:10.1093/annonc/mdx518
  • Keilholz U, Mehnert JM, Bauer S, et al. Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2019;7(1):12. DOI:10.1186/s40425-018-0459-y
  • Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218–1230. DOI:10.1056/NEJMoa2002788
  • Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), an anti–programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–3125. DOI:10.1200/JCO.2016.67.9761
  • Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956–965. DOI:10.1016/S1470-2045(16)30066-3
  • Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–1867. DOI:10.1056/NEJMoa1602252
  • Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(11):1506–1517. DOI:10.1016/S1470-2045(19)30626-6
  • Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191–1203. DOI:10.1056/NEJMoa2032125
  • El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–2502. DOI:10.1016/S0140-6736(17)31046-2
  • Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–952. DOI:10.1016/S1470-2045(18)30351-6
  • André T, Shiu K-K, 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
  • Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer. 2022;10(1):e003777. DOI:10.1136/jitc-2021-003777
  • 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
  • Eggermont AMM, Blank CU, Mandalà M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(5):643–654. DOI:10.1016/S1470-2045(21)00065-6
  • Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683–694. DOI:10.1056/NEJMoa2106391
  • Larkin J, Chiarion-Sileni V, Gonzalez R. Combined Nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):1270–1271.
  • Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020–2031. DOI:10.1056/NEJMoa1910231
  • Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883–895. DOI:10.1016/S1470-2045(16)30098-5
  • Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397(10272):375–386. DOI:10.1016/S0140-6736(20)32714-8
  • Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–1290. DOI:10.1056/NEJMoa1712126
  • Yau T, Park J-W, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90. DOI:10.1016/S1470-2045(21)00604-5
  • Reijers ILM, Menzies AM, van Akkooi ACJ, et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med. 2022;28(6):1178–1188. DOI:10.1038/s41591-022-01851-x
  • Maruhashi T, Sugiura D, Okazaki I, et al. LAG-3: from molecular functions to clinical applications. J Immunother Cancer. 2020;8(2):e001014. DOI:10.1136/jitc-2020-001014
  • Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5–6):176–189. DOI:10.18632/genesandcancer.180
  • Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24–34. DOI:10.1056/NEJMoa2109970
  • Woo S-R, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–927. DOI:10.1158/0008-5472.CAN-11-1620
  • Sauer N, Szlasa W, Jonderko L, et al. LAG-3 as a potent target for novel anticancer therapies of a wide range of tumors. Int J Mol Sci. 2022;23(17):9958. DOI:10.3390/ijms23179958
  • Jiang H, Ni H, Zhang P, et al. PD-L1/LAG-3 bispecific antibody enhances tumor-specific immunity. Oncoimmunology. 2021;10(1):1943180. DOI:10.1080/2162402X.2021.1943180
  • Sun J-M, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759–771. DOI:10.1016/S0140-6736(21)01234-4
  • Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27–40. DOI:10.1016/S0140-6736(21)00797-2
  • Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449–462. DOI:10.1056/NEJMoa2111380
  • Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973–1985. DOI:10.1056/NEJMoa2202170
  • Paz-Ares L, Ciuleanu T-E, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198–211. DOI:10.1016/S1470-2045(20)30641-0
  • Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7(5):387–401. DOI:10.1016/S2213-2600(19)30084-0
  • Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–2229. DOI:10.1056/NEJMoa1809064
  • Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929–1939. DOI:10.1016/S0140-6736(19)32222-6
  • Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–2121. DOI:10.1056/NEJMoa1809615
  • Lee C-H, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946–958. DOI:10.1016/S1470-2045(21)00241-2
  • Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–1127. DOI:10.1056/NEJMoa1816714
  • Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829–841. DOI:10.1056/NEJMoa2026982
  • Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–1115. DOI:10.1056/NEJMoa1816047
  • Taube JM, Klein A, Brahmer JR, et al. 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(19):5064–5074. DOI:10.1158/1078-0432.CCR-13-3271
  • Cottrell T, Taube JM. PD-L1 and emerging biomarkers in PD-1/PD-L1 blockade therapy. Cancer J. 2018;24(1):41–46.
  • Sun L, Zhang L, Yu J, et al. Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis. Sci Rep. 2020;10(1):2083. DOI:10.1038/s41598-020-58674-4
  • Grasso CS, Tsoi J, Onyshchenko M, et al. Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma. Cancer Cell. 2020;38(4):500–515.e3. DOI:10.1016/j.ccell.2020.08.005
  • Johnson DB, Bordeaux J, Kim JY, et al. Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO-1 predicts improved outcomes of anti–PD-1 therapies in metastatic melanoma. Clin Cancer Res. 2018;24(21):5250–5260. DOI:10.1158/1078-0432.CCR-18-0309
  • Johnson DB, Estrada MV, Salgado R, et al. Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun. 2016;7(1):10582. DOI:10.1038/ncomms10582
  • Postow MA, Hellmann MD, Adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(12):158–168. DOI:10.1056/NEJMra1703481
  • Becerra MVS, Martinez-Cabañes R, Gonzalez-Lopez A, et al. 204P Immune-related adverse events (IrAes) as a predictor of response to immunotherapy in patients with lung cancer. J Thorac Oncol. 2021;16:S808–809.
  • Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. JCO. 2017;35(7):785–792. DOI:10.1200/JCO.2015.66.1389
  • Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors – a systematic review and meta-analysis. Cancer Treat Rev. 2021;92:102134.
  • Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151(11):1206–1212. DOI:10.1001/jamadermatol.2015.1916
  • Quach HT, Dewan AK, Davis EJ, et al. Association of anti–programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma. JAMA Oncol. 2019;5(6):906–908. DOI:10.1001/jamaoncol.2019.0046
  • Tang K, Seo J, Tiu BC, et al. Association of cutaneous immune-related adverse events with increased survival in patients treated with anti–programmed cell death 1 and anti–programmed cell death ligand 1 therapy. JAMA Dermatol. 2022;158(2):189–193. DOI:10.1001/jamadermatol.2021.5476
  • Dousset L, Pacaud A, Barnetche T, et al. Analysis of tumor response and clinical factors associated with vitiligo in patients receiving anti-programmed cell death-1 therapies for melanoma: a cross-sectional study. JAAD Int. 2021;5:112–120.
  • Nakano E, Takahashi A, Namikawa K, et al. Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: a single institutional retrospective study. J Dermatol. 2020;47(6):622–628. DOI:10.1111/1346-8138.15309
  • Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103. DOI:10.1126/science.aan4236
  • Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–108. DOI:10.1126/science.aao3290
  • Routy B, Gopalakrishnan V, Daillère R, et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat Rev Clin Oncol. 2018;15(6):382–396. DOI:10.1038/s41571-018-0006-2
  • Shiroyama T, Nagatomo I, Koyama S, et al. Impact of sarcopenia in patients with advanced non–small cell lung cancer treated with PD-1 inhibitors: a preliminary retrospective study. Sci Rep. 2019;9(1):2447. DOI:10.1038/s41598-019-39120-6
  • McQuade JL, Daniel CR, Hess KR, et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 2018;19(3):310–322. DOI:10.1016/S1470-2045(18)30078-0
  • Rogado J, Romero-Laorden N, Sanchez-Torres JM, et al. Effect of excess weight and immune-related adverse events on the efficacy of cancer immunotherapy with anti-PD-1 antibodies. Oncoimmunology. 2020;9(1):1751548. DOI:10.1080/2162402X.2020.1751548
  • Thommen DS, Schumacher TN. T cell dysfunction in cancer. Cancer Cell. 2018;33(4):547–562.
  • Miller BC, Sen DR, Abosy RA, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326–336. DOI:10.1038/s41590-019-0312-6
  • Im SJ, Hashimoto M, Gerner MY, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417–421. DOI:10.1038/nature19330
  • Yu Y, Zhou Y, Zhang X, et al. Immune checkpoint inhibitors in the treatment of patients with cancer and preexisting psoriasis: a systematic review and meta-analysis of observational studies. Front Oncol. 2022;12:934093.
  • Alexander S, Swami U, Kaur A, et al. Safety of immune checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease. Ann Transl Med. 2021;9(12):1033. DOI:10.21037/atm-20-8124
  • Higgins JP, Trinh AV, Watson ML, et al. A safety analysis of programmed death 1 pathway inhibitors in patients with solid tumor malignancies and preexisting autoimmune disease. J Clin Rheumatol. 2022;28(7):338–345. DOI:10.1097/RHU.0000000000001863
  • Khoja L, Day D, Chen T-W, et al. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol. 2017;28(10):2377–2385. DOI:10.1093/annonc/mdx286
  • Yan Y-D, Zhao Y, Zhang C, et al. Toxicity spectrum of immunotherapy in advanced lung cancer: a safety analysis from clinical trials and a pharmacovigilance system. eClinicalmedicine. 2022;50:101535.
  • Tarhini AA, Lee SJ, Hodi FS, et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon Alfa-2b for resected high-risk melanoma: north American intergroup E1609. J Clin Oncol. 2020;38(6):567–575. DOI:10.1200/JCO.19.01381
  • Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol. 2019;37(11):867–875. DOI:10.1200/JCO.18.01998
  • Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of Anti–PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454. DOI:10.1056/NEJMoa1200690
  • Zhou X, Yao Z, Bai H, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol. 2021;22(9):1265–1274. DOI:10.1016/S1470-2045(21)00333-8
  • Park R, Lopes L, Cristancho CR, et al. Treatment-related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis. Front Oncol. 2020;10 [[cited 2022 Sep 25]]. InternetAvailable from: https://www.frontiersin.org/articles/10.3389/fonc.2020.00258
  • Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–1356. DOI:10.1056/NEJMoa1709684
  • Wang DY, Salem J-E, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–1728. DOI:10.1001/jamaoncol.2018.3923
  • Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. JCO. 2012;30(21):2691–2697.
  • Tang S-Q, Tang L-L, Mao Y-P, et al. The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: a pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat. 2021;53(2):339–354. DOI:10.4143/crt.2020.790
  • Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–1755. DOI:10.1056/NEJMoa1609214
  • Berner F, Bomze D, Diem S, et al. Association of checkpoint inhibitor–induced toxic effects with shared cancer and tissue antigens in non–small cell lung cancer. JAMA Oncol. 2019;5(7):1043–1047. DOI:10.1001/jamaoncol.2019.0402
  • Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):306.
  • Iwama S, De Remigis A, Callahan MK, et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014;6(230):230ra45. DOI:10.1126/scitranslmed.3008002
  • Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, et al. A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis. Nat Med. 2019;25(8):1243–1250. DOI:10.1038/s41591-019-0523-2
  • Lim SY, Lee JH, Gide TN, et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving Anti-PD-1–based immunotherapy. Clin Cancer Res. 2019;25(5):1557–1563. DOI:10.1158/1078-0432.CCR-18-2795
  • Kobayashi M, Numakura K, Hatakeyama S, et al. Severe immune-related adverse events in patients treated with nivolumab for metastatic renal cell carcinoma are associated with PDCD1 polymorphism. Genes (Basel). 2022;13(7):1204. DOI:10.3390/genes13071204
  • Johnson DB, Nebhan CA, Moslehi JJ, et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254–267. DOI:10.1038/s41571-022-00600-w
  • Mor A, Strazza M. Bridging the gap: connecting the mechanisms of immune-related adverse events and autoimmunity through PD-1. Front Cell Dev Biol. 2022;9. [[cited 2022 Sep 23]]. InternetAvailable from: https://www.frontiersin.org/articles/10.3389/fcell.2021.790386
  • Das R, Bar N, Ferreira M, et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest. 2018;128(2):715–720. DOI:10.1172/JCI96798
  • von Itzstein MS, Khan S, Gerber DE, et al. Investigational biomarkers for checkpoint inhibitor immune-related adverse event prediction and diagnosis. Clin Chem. 2020;66(6):779–793.
  • Schindler K, Harmankaya K, Kuk D, et al. Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab. JCO. 2014;32(15_suppl):9096. DOI:10.1200/jco.2014.32.15_suppl.9096
  • Bastacky ML, Wang H, Fortman D, et al. Immune-related adverse events in PD-1 treated melanoma and impact upon anti-tumor efficacy: a real world analysis. Front Oncol. 2021;11:749064.
  • Kimbara S, Fujiwara Y, Iwama S, et al. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab. Cancer Sci. 2018;109(11):3583–3590. DOI:10.1111/cas.13800
  • Ghosh N, Postow M, Zhu C, et al. Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition. J Immunother Cancer. 2022;10(1):e004008. DOI:10.1136/jitc-2021-004008
  • Castel-Ajgal Z, Goulvestre C, Zaibet S, et al. Preexisting autoantibodies and immune related adverse events in metastatic urothelial carcinoma patients treated by pembrolizumab. Clinical Genitourinary Cancer [Internet]. 2022 [cited 2022 Aug 11]; Available from: https://www.sciencedirect.com/science/article/pii/S1558767322000799.
  • Andrews MC, Duong CPM, Gopalakrishnan V, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021;27(8):1432–1441. DOI:10.1038/s41591-021-01406-6
  • Simpson RC, Shanahan ER, Batten M, et al. Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome. Nat Med. 2022;28(11):2344–2352.
  • Owen CN, Bai X, Quah T, et al. Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma. Ann Oncol. 2021;32(7):917–925. DOI:10.1016/j.annonc.2021.03.204
  • Couey MA, Bell RB, Patel AA, et al. Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance. J Immunother Cancer. 2019;7(1):165. DOI:10.1186/s40425-019-0645-6
  • Lozano AX, Chaudhuri AA, Nene A, et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nat Med. 2022;28(2):353–362. DOI:10.1038/s41591-021-01623-z
  • Weber JS, Schadendorf D, Del Vecchio M, et al. Adjuvant therapy of nivolumab combined with ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or stage IV melanoma (CheckMate 915). JCO. 2022;41(3):517–527. JCO.22.00533.
  • Jing Y, Yang J, Johnson DB, et al. Harnessing big data to characterize immune-related adverse events. Nat Rev Clin Oncol. 2022;19(4):269–280. DOI:10.1038/s41571-021-00597-8
  • Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591–5598. DOI:10.1158/1078-0432.CCR-09-1024
  • Hailemichael Y, Johnson DH, Abdel-Wahab N, et al. Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer Cell. 2022;40(5):509–523.e6. DOI:10.1016/j.ccell.2022.04.004
  • Dimitriou F, Hogan S, Menzies AM, et al. Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy. Eur J Cancer. 2021;157:214–224.
  • Darnell EP, Mooradian MJ, Baruch EN, et al. Immune-related adverse events (irAes): diagnosis, management, and clinical pearls. Curr Oncol Rep. 2020;22(4):39. DOI:10.1007/s11912-020-0897-9
  • Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.
  • Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: eSMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–142.
  • Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020. J Natl Compr Canc Netw. 2020;18(3):230–241. DOI:10.6004/jnccn.2020.0012
  • Society for immunotherapy of cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events | Journal for ImmunoTherapy of Cancer [Internet]. [cited 2022 Sep 25]. Available from: https://jitc.bmj.com/content/9/6/e002435
  • Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update | Journal of Clinical Oncology [Internet]. [cited 2022 Sep 25]. Available from: https://ascopubs-org.proxy.library.vanderbilt.edu/doi/full/10.1200/JCO.21.01440
  • Common terminology criteria for adverse events (CTCAE). 2017;p. 155.
  • Johnson DB, Reynolds KL, Sullivan RJ, et al. Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research. Lancet Oncol. 2020;21(8):e398–404. DOI:10.1016/S1470-2045(20)30107-8
  • Luo J, Beattie JA, Fuentes P, et al. Beyond steroids: immunosuppressants in steroid-refractory or resistant immune-related adverse events. J Thorac Oncol. 2021;16(10):1759–1764. DOI:10.1016/j.jtho.2021.06.024
  • Beattie J, Rizvi H, Fuentes P, et al. Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade. J Immunother Cancer. 2021;9(2):e001884. DOI:10.1136/jitc-2020-001884
  • Dougan M, Blidner AG, Choi J, et al. Multinational association of support care cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors. Support Cancer Ther. 2020;28(12):6129–6143. DOI:10.1007/s00520-020-05707-3
  • Johnson DH, Zobniw CM, Trinh VA, et al. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer. 2018;6(1):103. DOI:10.1186/s40425-018-0412-0
  • Nguyen LS, Bretagne M, Arrondeau J, et al. Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept. J Immunother Cancer. 2022;10(4):e004699. DOI:10.1136/jitc-2022-004699
  • Salem J-E, Allenbach Y, Vozy A, et al. Abatacept for severe immune checkpoint inhibitor–associated myocarditis. N Engl J Med. 2019;380(24):2377–2379. DOI:10.1056/NEJMc1901677
  • Wei SC, Meijers WC, Axelrod ML, et al. A genetic mouse model recapitulates immune checkpoint inhibitor–associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov. 2021;11(3):614–625. DOI:10.1158/2159-8290.CD-20-0856
  • Jiang C, Zhang L, Xu X, et al. Engineering a smart agent for enhanced immunotherapy effect by simultaneously blocking PD‐L1 and CTLA‐4. Adv Sci. 2021;8(20):2102500. DOI:10.1002/advs.202102500
  • Gan X, Shan Q, Li H, et al. An anti-CTLA-4 heavy chain–only antibody with enhanced treg depletion shows excellent preclinical efficacy and safety profile. Proc Natl Acad Sci USA. 2022;119(32):e2200879119.
  • Chung CK, Fransen MF, van der Maaden K, et al. Thermosensitive hydrogels as sustained drug delivery system for CTLA-4 checkpoint blocking antibodies. JControlled Release. 2020;323:1–11.
  • Guo M, VanderWalde AM, Yu X, et al. Immune checkpoint inhibitor rechallenge safety and efficacy in stage IV non-small cell lung cancer patients after immune-related adverse events. Clin Lung Cancer. 2022;23:686–693.
  • Yang J, Zeng R, Zhou J, et al. Efficacy, prognosis and safety analysis of anti-PD-1/PD-L1 inhibitor rechallenge in advanced lung cancer patients: a cohort study. Transl Lung Cancer Res. 2022;11(6):1038–1050. DOI:10.21037/tlcr-22-360
  • Ngamphaiboon N, Ithimakin S, Siripoon T, et al. Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis. BMC Cancer. 2021;21(1):1275. DOI:10.1186/s12885-021-09003-z
  • Albandar HJ, Fuqua J, Albandar JM, et al. Immune-related adverse events (irAE) in cancer immune checkpoint inhibitors (ICI) and survival outcomes correlation: to rechallenge or not? Cancers (Basel). 2021;13(5):989. DOI:10.3390/cancers13050989
  • Allouchery M, Lombard T, Martin M, et al. Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade ≥2 immune-related adverse events in patients with cancer. J Immunother Cancer. 2020;8(2):e001622. DOI:10.1136/jitc-2020-001622

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