Aseptic meningitis induced by monoclonal antibodies used in cancer treatment: a systematic review
Abstract
Background and purpose: Monoclonal antibodies (MAbs) have revolutionized cancer treatment but are associated with a spectrum of adverse events, including neurological complications. Understanding the mechanism and management of complications is crucial for optimizing patient care. The present systematic review aimed to identify case reports of MAbs used for cancer treatment that resulted in aseptic meningitis (AM).
Methods: Databases including Google Scholar, PubMed, and Scopus were searched for studies published until March 2024 (updated in May 2025). The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the quality of case report studies, and the methodological quality of the included studies was considered acceptable.
Findings/Results: In total, 32 articles were analyzed in the present systematic review. Cetuximab had the highest reported incidence of AM, while rituximab, daratumumab, and apolizumab had the lowest prevalence. The quality of the studies was also acceptable.
Conclusion and implications: AM appears to occur more frequently with monoclonal antibodies than with conventional drug structures. Prompt recognition of the underlying mechanisms can help physicians manage these complications more effectively.
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Rahimmanesh I, Esmaili Y, Ghafouri E, Hejazi SH, Khanahmad H. Enhanced in vivo anti-tumor efficacy of whole tumor lysate in combination with whole tumor cell-specific polyclonal antibody. Res Pharm Sci.2023;18(2):138-148.DOI: 10.4103/1735-5362.367793.
Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017;74(10):1216-1222. DOI: 10.1001/jamaneurol.2017.1912.
Momenzadeh M, Aria A, Ghadimi K, Moghaddas A. Acetyl-L-carnitine for the prevention of taxane-induced neuropathy in patients with breast cancer: a systematic review and meta-analysis. Res Pharm Sci. 2023;18(2):112-120. DOI: 10.4103/1735-5362.367791.
Gottenberg JE, Cinquetti G, Larroche C, Combe B, Hachulla E, Meyer O, et al. Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: results in 78 patients of the autoimmune and rituximab registry. Ann Rheum Dis. 2013;72(6):1026-1031. DOI: 10.1136/annrheumdis-2012-202293.
Nejati M, Soheili M, Salami M, Khedri M. The effect of redox bacteria on the programmed cell death-1 cancer immunotherapy. Res Pharm Sci. 2024;19(2):228-237.DOI: 10.4103/RPS.RPS_28_23.
Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:1-8. DOI: 10.1016/j.ejca.2016.12.001.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. DOI: 10.1056/NEJMoa1003466.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. DOI: 10.1056/NEJMoa1507643.
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330. DOI: 10.1056/NEJMoa1412082.
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908-918. DOI: 10.1016/S1470-2045(15)00083-2.
Riggs CE. Panitumumab treatment of head and neck cancer after cetuximab-induced aseptic meningitis: case report. J Clin Oncol. 2011;29(15_Suppl):e16033. DOI: 10.1200/jco.2011.29.15_suppl.e16033.
Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825-830. DOI: 10.1097/CJI.0b013e318156e47e.
Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18(10): 2127-2133. DOI: 10.11124/JBISRIR-D-19-00099.
Rogers JE, Law L, Shroff R. Successful panitumumab administration after cetuximab-induced aseptic meningitis: a case report and review. J Hematol Oncol Pharm. 2014;4(1):18-21.
Feinstein TM, Gibson MK, Argiris A. Cetuximab-induced aseptic meningitis. Ann Oncol. 2009;20(9):1609-1610. DOI: 10.1093/annonc/mdp382.
Nagovskiy N, Agarwal M, Allerton J. Cetuximab-induced aseptic meningitis. J Thorac Oncol. 2010;5(5):751,1-1. DOI: 10.1097/JTO.0b013e3181d408bc.
Givens P, Velez AP, Sandin RL, Quilitz RE, Greene JN. Development of enteroviral aseptic meningitis after rituximab treatment of non-Hodgkin lymphoma. Infect Dis Clin Pract (Baltim Md). 2012;20(4): 291-293.DOI: 10.1097/IPC.0b013e3182506ea0.
Emani MK, Zaiden RA Jr. Aseptic meningitis: a rare side effect of cetuximab therapy. J Oncol Pharm Pract. 2013;19(2):178-180. DOI: 10.1177/1078155212447973.
Prasanna D, Elrafei T, Shum E, Strakhan M. More than a headache: a case of cetuximab-induced aseptic meningitis. BMJ Case Rep. 2015;2015:bcr2015209622,1-3. DOI: 10.1136/bcr-2015-209622.
Ulrich A, Weiler S, Weller M, Rordorf T, Tarnutzer AA. Cetuximab induced aseptic meningitis. J Clin Neurosci. 2015;22(6):1061-1063. DOI: 10.1016/j.jocn.2014.11.034.
Maritaz C, Metz C, Baba-Hamed N, Jardin-Szucs M, Deplanque G. Cetuximab-induced aseptic meningitis: case report and review of a rare adverse event. BMC Cancer. 2016;16:384,1-5. DOI: 10.1186/s12885-016-2434-7.
Oishi K, Nakao M, Maeda S, Matsushita T, Ikeda T, Yamada T, et al. A case of aseptic meningitis without neck rigidity occurring in a metastatic melanoma patient treated with ipilimumab. Eur J Dermatol. 2017;27(2):193-194. DOI: 10.1684/ejd.2016.2943.
Reddy K, Htut M, Krishnan A, Dadwal SS. Aseptic meningitis as a complication of daratumumab therapy. Clin Lymphoma Myeloma Leuk. 2018;18(8):e333-e335. DOI: 10.1016/j.clml.2018.05.018.
Inui G, Funaki Y, Makino H, Touge H, Arai K, Kuroda K, et al. Pembrolizumab-induced aseptic meningitis in a patient with non-small cell lung cancer: a case report and literature review of aseptic meningitis as an immune-related adverse event. Mol Clin Oncol. 2022;17(1):120,1-9. DOI: 10.3892/mco.2022.2553.
Vulsteke CA, Joosens E, De Klippel N, Mebis J. Aseptic meningitis as a rare but serious side effect of cetuximab therapy. Belg J Med Oncol. 2010;4: 257-259.
Rohrer CL, Grullon Z, George SK, Castillo R, Karasiewicz K. A case of aseptic meningitis in a cetuximab-experienced patient with metastatic colon cancer. J Oncol Pharm Pract. 2018;24(8):632-633. DOI: 10.1177/1078155217739685.
Jäger J, Sprügel M, Brunner T, Uhl M, Schwab S, Vitali F, et al. Cetuximab-induced aseptic meningitis in a patient with colorectal cancer: a case report and review of literature. Case Rep Neurol. 2022;14(3):475-482. DOI: 10.1159/000527075.
Al-Khateeb W, Jarad J, Kim Y, Battisti R. Long-term nivolumab treatment possibly associated with aseptic meningitis. BMJ Case Rep. 2024;17(2):e258141,1-4. DOI: 10.1136/bcr-2023-258141.
Takamatsu D, Furubayashi N, Negishi T, Ieiri K, Inoue T, Tsukino K, et al. Relapse of aseptic meningitis induced by ipilimumab and nivolumab therapy for metastatic renal cell carcinoma: a case report. Mol Clin Oncol. 2019;11(6):590-594. DOI: 10.3892/mco.2019.1929.
Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13(4):278-280. DOI: 10.1136/practneurol-2012-000447.
Cordes LM, Davarpanah NN, Reoma LB, Gasmi B, Quezado M, Khan OI, et al. Neurotoxicities associated with checkpoint inhibitors: two case reports and a review of the literature. Clin Case Rep. 2019;8(1):24-32. DOI: 10.1002/ccr3.2534.
Lima G, Kahn A, Sama S, Savage J. Aseptic meningitis as an immune-related adverse event after pembrolizumab. Case Rep Oncol Med. 2019;2019:7183747,1-2.DOI: 10.1155/2019/7183747.
Toyozawa R, Haratake N, Toyokawa G, Matsubara T, Takamori S, Miura N, et al. Atezolizumab-induced aseptic meningitis in patients with NSCLC. JTO Clin Res Rep. 2020;1(1):100012. DOI: 10.1016/j.jtocrr.2020.100012.
Kaur S, Khatun H, Kumar A, Ellis M, Mehta D, Guron G. Cetuximab induced aseptic meningitis: a rare side effect. J Cancer Sci Ther. 2018;10(8): 211-213. DOI: 10.4172/1948-5956.1000546.
Katakura Y, Kimura T, Kusano T, Tatsumi F, Iwamoto Y, Sanada J, et al. Case report: a variety of immune-related adverse events triggered by immune checkpoint inhibitors in a subject with malignant melanoma: destructive thyroiditis, aseptic meningitis and isolated ACTH deficiency. Front Endocrinol (Lausanne). 2021;12:722586,1-5. DOI: 10.3389/fendo.2021.722586.
Tonk EHJ, Snijders TJ, Koldenhof JJ, van Lindert ASR, Suijkerbuijk KPM. Cerebrospinal fluid lymphocytosis: a hallmark of neurological complications during checkpoint inhibition. Eur J Cancer. 2019;121:1-3. DOI: 10.1016/j.ejca.2019.08.004.
Kuroda R, Nakagawa H, Uchida Y, Narumiya K, Tsunoda Y, Yamaguchi M, et al. Immune-related aseptic meningitis diagnosed by Cube FLAIR on enhanced magnetic resonance imaging for a lung cancer patient administered atezolizumab: a case report. Respirol Case Rep. 2023;11(2):e01076,1-3.DOI: 10.1002/rcr2.1076.
Kawanaka H, Tajiri K, Muraishi N, Murayama A, Nukui T, Yasuda I. A case of immune-related aseptic meningitis during atezolizumab plus bevacizumab for hepatocellular carcinoma. Case Rep Gastroenterol. 2024;18(1):8-13. DOI: 10.1159/000535476.
Spain L, Walls G, Julve M, O’Meara K, Schmid T, Kalaitzaki E, et al. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol. 2017;28(2):377-385. DOI: 10.1093/annonc/mdw558.
Lin TS, Stock W, Xu H, Phelps MA, Lucas MS, Guster SK, et al. A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped-up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia. Leuk Lymphoma. 2009;50(12):1958-1963. DOI: 10.3109/10428190903186486.
Kako S, Gomyo A, Akahoshi Y, Harada N, Kameda K, Ugai T, et al. Haploidentical transplantation using low‐dose alemtuzumab: comparison with haploidentical transplantation using low‐dose thymoglobulin. Eur J Haematol. 2019;102(3): 256-264. DOI: 10.1111/ejh.13204.
Wagner TD, Yang GY. Cetuximab: its use in combination with radiation therapy and chemo-therapy in the multimodality treatment of head and neck cancer. Recent Pat Anticancer Drug Discov. 2008;3(2):76-83. DOI: 10.2174/157489208784638776.
Štulhofer Buzina D, Martinac I, Ledić Drvar D, Čeović R, Bilić I, Marinović B. Adverse reaction to cetuximab, an epidermal growth factor receptor inhibitor. Acta Dermatovenerol Croat. 2016;24(1):70-72. PMID: 27149134.
Kranick S, Lehky T, Chung C, Kang H. Chronic immune-mediated demyelinating polyneuropathy after cetuximab (P4.122). Neurology. 2014;82(10_supplement):P4.122. DOI: 10.1212/WNL.82.10_supplement.P4.122.
Tridente G. Adverse Events with Biomedicines: prevention through understanding. 1th ed. Milano: Springer; 2013. pp. 351-368.DOI: 10.1007/978-88-470-5313-7.
Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapy--rare but there! Leuk Lymphoma. 2009;50(7):1083-1095. DOI: 10.1080/10428190902934944.
Farzadfard F, Poursadeghfard M, Ashjazadeh N. Infusion-related, short-term, and delayed side effects of rituximab in multiple sclerosis and neuromyelitis optica spectrum disorder. Shiraz E-Med J. 2021;22(3):e101625,1-8. DOI: 10.5812/semj.101625.
Graça L, Alves J, Nuak J, Sarmento A. Immunoglobulin-induced aseptic meningitis: a case report. BMC Neurol. 2018;18(1):97,1-3. DOI: 10.1186/s12883-018-1102-8.
Cameron F, Whiteside G, Perry C. Ipilimumab: first global approval. Drugs. 2011;71(8):1093-1104. DOI: 10.2165/11594010-000000000-00000.
Witges K, Shafer LA, Zarychanski R, Abou-Setta AM, Rabbani R, Dingwall O, et al. Ipilimumab-induced enterocolitis: a systematic review and meta-analysis. Drug Saf. 2020, 43(12):1255-1266.DOI: 10.1007/s40264-020-00979-4.
Venditti O, De Lisi D, Caricato M, Caputo D, Capolupo GT, Taffon C, et al. Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis. BMC Cancer. 2015;15:87,1-5. DOI: 10.1186/s12885-015-1074-7.
Dika E, Ravaioli GM, Fanti PA, Piraccini BM, Lambertini M, Chessa MA, et al. Cutaneous adverse effects during ipilimumab treatment for metastatic melanoma: a prospective study. Eur J Dermatol. 2017;27(3):266-270. DOI: 10.1684/ejd.2017.3023.
Chintalacheruvu LM, Naha K, Chilluru VK, Doll DC. Review of neurological side effects associated with checkpoint inhibitor therapy in cancer patients. J Clin Oncol. 2020;38(5_Suppl):72-72.DOI: 10.1200/JCO.2020.38.5_suppl.72.
Ganta N, Alnabwani D, Keating S, Patel V, Bommu VJL, Dawoud R, et al. Rare adverse events related to nivolumab, an immune checkpoint inhibitor: a case series. Cureus. 2022;14(2):e22070,1-4. DOI: 10.7759/cureus.22070.
Zhao B, Zhao H, Zhao J. Serious adverse events and fatal adverse events associated with nivolumab treatment in cancer patients: nivolumab-related serious/fatal adverse events. J Immunother Cancer. 2018;6(1):101,1-12. DOI: 10.1186/s40425-018-0421-z.
Numakura K, Sekine Y, Hatakeyama S, Muto Y, Sobu R, Kobayashi M, et al. Primary resistance to nivolumab plus ipilimumab therapy in patients with metastatic renal cell carcinoma. Cancer Med. 2023;12(16):16837-16845. DOI: 10.1002/cam4.6306.
Alden SL, Lim M, Kao C, Shu D, Singal AG, Noonan A, et al. Salvage ipilimumab plus nivolumab after anti-PD-1/PD-L1 therapy in advanced hepatocellular carcinoma. Cancer Res Commun. 2023;3(7):1312-1317. DOI: 10.1158/2767-9764.CRC-23-0072.
Vázquez-Montero L, de la Gala MDCÁ, de la Cruz-Merino L. Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations. Front Oncol. 2023;13:1187840,1-9.DOI: 10.3389/fonc.2023.1187840.
Somekawa K, Horita N, Kaneko A, Tagami Y, Fukuda N, Matsumoto H, et al. Adverse events induced by nivolumab and ipilimumab combination regimens. Ther Adv Med Oncol. 2022;14:17588359211058393,1-12. DOI: 10.1177/17588359211058393.
Zhao X, Gao F, Yang J, Fan H, Xie Q, Jiang K, et al. Risk of adverse events in cancer patients receiving nivolumab with ipilimumab: a meta-analysis. Front Oncol. 2022;12:877434. DOI: 10.3389/fonc.2022.877434.
Arora G, Lising J. LBODP011 pembrolizumab-induced hypophysitis and resultant isolated ACTH deficiency presenting as secondary adrenal insufficiency. J Endocr Soc. 2022;6(Suppl 1): A42, 1-1.DOI: 10.1210/jendso/bvac150.087.
Albarrán V, Chamorro J, Rosero DI, Saavedra C, Soria A, Carrato A, et al. Neurologic toxicity of immune checkpoint inhibitors: a review of literature. Front Pharmacol. 2022;13:774170. DOI: 10.3389/fphar.2022.774170.
Raedler LA. Darzalex (daratumumab): first anti-CD38 monoclonal antibody approved for patients with relapsed multiple myeloma. Am Health Drug Benefits. 2016;9(Spec Feature):70-73.PMID: 27668047.
Kareem SS, Viswanathan N, Sahebjam S, Tran ND, Gatewood T, Tobon K, et al. Leukoencephalopathy during daratumumab-based therapy: a case series of two patients with multiple myeloma. Onco Targets Ther. 2022;15:953-962. DOI: 10.2147/OTT.S365657.
Krishnamurthy A, Jimeno A. Atezolizumab: a novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers. Drugs Today (Barc). 2017;53(4):217-237. DOI: 10.1358/dot.2017.53.4.2589163.
Laserna A, Tummala S, Patel N, El Hamouda DEM, Gutiérrez C. Atezolizumab-related encephalitis in the intensive care unit: case report and review of the literature. SAGE Open Med Case Rep. 2018;6:2050313X18792422,1-4. DOI: 10.1177/2050313X18792422.
Ibrahim EY, Zhao WC, Mopuru H, Janowiecki C, Regelmann DJ. Hope, cure, and adverse effects in immunotherapy: atezolizumab-associated encephalitis in metastatic small cell lung cancer-a case report and literature review. Case Rep Neurol. 2022;14(3):366-371. DOI: 10.1159/000526248.
Fracasso PM, Goodner SA, Wildi JD, Naughton MJ, Linette GP, Govindan R, et al. A phase I study of apolizumab, an anti-HLA-DR ß-chain monoclonal antibody, in patients with solid tumor malignancies. Am J Clin Oncol. 2022;45(7): 294-297. DOI: 10.1097/COC.0000000000000924.
Alsalem AN, Scarffe LA, Briemberg HR, Aaroe AE, Harrison RA. Neurologic complications of cancer immunotherapy. Curr Oncol. 2023;30(6):5876-5897.DOI: 10.3390/curroncol30060440.
Alinari L, Lapalombella R, Andritsos L, Baiocchi RA, Lin TS, Byrd JC. Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia. Oncogene. 2007;26(25):3644-3653. DOI: 10.1038/sj.onc.1210380.
Osterborg A, Karlsson C, Lundin J, Kimby E, Mellstedt H. Strategies in the management of alemtuzumab-related side effects. Semin Oncol. 2006;33(2 Suppl 5):S29-S35. DOI: 10.1053/j.seminoncol.2006.01.027.
Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med. 1994;121(4):259-262. DOI: 10.7326/0003-4819-121-4-199408150-00004.
Hamrock DJ. Adverse events associated with intravenous immunoglobulin therapy. Int Immunopharmacol. 2006;6(4):535-542. DOI: 10.1016/j.intimp.2005.11.015.
Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109-1117. DOI: 10.1056/NEJMoa074943.
Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745,1-17. DOI: 10.1371/journal.pone.0053745.
Kopecký J, Kubeček O, Geryk T, Slováčková B, Hoffmann P, Žiaran M, et al. Nivolumab-induced encephalopathy in a man with metastatic renal cell cancer: a case report. J Med Case Rep. 2018;12(1):262,1-8. DOI: 10.1186/s13256-018-1786-9.
Mizukami T, Masuda T, Kimura N, Uchida H, Jikumaru M, Hanaoka T, et al. Cerebrospinal fluid Interleukin-6 in immune checkpoint inhibitor-induced autoimmune meningoencephalitis. Tohoku J Exp Med. 2022;258(2):159-165. DOI: 10.1620/tjem.2022.J071.
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