1. INTRODUCTION
Aseptic meningitis (AM) is characterized by inflammation of the meninges and presents with symptoms such as severe headache, fever, neck stiffness, and photophobia. AM is a rare but serious adverse event associated with the use of monoclonal antibodies (MAbs) in cancer treatment. MAbs have revolutionized the field of oncology offering targeted therapy with fewer systemic side effects compared to traditional chemotherapy ( 1 , 2 , 3 ).
The development of AM in cancer patients receiving MAbs has been reported in the literature, with varying incidences depending on the specific MAbs used. The pathophysiology of AM induced by MAbs is not fully understood, but it is thought to be related to an immune-mediated response triggered by the antibodies ( 4 , 5 , 6 ).
Several MAbs have been implicated in the development of AM, including rituximab, an anti- CD20 antibody used in the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL), and ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor used in the treatment of advanced melanoma ( 7 ). The incidence of AM associated with these agents varies, with reported rates ranging from 0.5% to 3% for rituximab and approximately 3% for ipilimumab. Other MAbs, such as nivolumab and pembrolizumab, which are immune checkpoint inhibitors used in the treatment of various solid tumors, have also been linked to AM, albeit rarely ( 8 , 9 , 10 ).
Given the expanding use of MAbs in cancer treatment, healthcare providers must be aware of the potential for AM as a rare but important adverse event. This article aimed to review the current literature on AM induced by MAbs used in cancer treatment, including incidence, clinical presentation, pathophysiology, diagnosis, and management. By increasing awareness and understanding of this complication, clinicians may optimize the safe and effective use of MAbs in the oncology setting.
2. METHODS
2.1. Data sources
The present systematic review aimed to identify and analyze AM induced by MAbs in cancer treatment. The report was prepared based on the Preferred Reporting Items for systematic reviews and meta-analyses (PRISMA) checklist. The databases, including Google Scholar, PubMed, and Scopus, were searched for studies published until March 2024. Each was updated in May 2025.
2.2. Search strategy
The keywords used in the PubMed database were the following: aseptic meningitis, monoclonal antibody, cancer, and case report. The following MeSH terms were used: (aseptic meningitis) AND (monoclonal antibody OR antibody, monoclonal OR monoclonal antibodies) AND (tumors OR neoplasia OR neoplasias OR neoplasm OR tumor OR cancer OR cancers OR malignant neoplasm OR malignancy OR malignancies OR malignant neoplasms OR neoplasm, malignant OR neoplasms, malignant OR benign OR neoplasms OR neoplasms, benign OR neoplasm, benign OR benign neoplasm). In the Scopus database, the same keywords were utilized in the “article title, abstract, keywords” field. Moreover, the same keywords were used as a search query in the advanced search of Google Scholar.
2.3. Eligibility criteria
The inclusion criteria for this study were as follows: (a) case reports or case series, (b) reports addressing AM associated with the use of MAbs in cancer management, (c) availability of full text (except for two articles ( 11 , 12 ). Records were excluded if they were (a) non-English, (b) AM induced by traditional chemotherapy, and (c) review or meta-analysis studies, letters to the editor, clinical trials (except those mentioned in Table 1 as they contained individual information of affected patients), and qualitative studies.
Table 1.
JBI critical appraisal checklist for case reports.
Y, Yes; N, no; UC, uncertain.
| Study | Were the patient’s demographic characteristics clearly described? | Was the patient's history clearly described and presented as a timeline? | Was the current clinical condition of the patient on presentation clearly described? | Were diagnostic tests or assessment methods and the results clearly described? | Were the intervention(s) or treatment procedure(s) clearly described? | Was the post-intervention clinical condition clearly described? | Were adverse events (harms) or unanticipated events identified and described? | Does the case report provide takeaway lessons? | Overall appraisal |
| Rogers et al. ( 14 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Feinstein et al. ( 15 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Nagovskiy et al. ( 16 ) | Y | Y | Y | Y | N | Y | Y | Y | Include |
| Givens et al. ( 17 ) | Y | Y | Y | Y | UC | N | Y | Y | Include |
| Emani and Zaiden ( 18 ) | Y | Y | Y | Y | Y | UC | Y | Y | Include |
| Prasanna et al. ( 19 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Ulrich et al. ( 20 ) | Y | Y | Y | Y | Y | UC | Y | Y | Include |
| Maritaz et al. ( 21 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Oishi et al. ( 22 ) | Y | Y | Y | Y | Y | N | Y | Y | Include |
| Reddy et al. ( 23 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Inui et al. ( 24 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Vulsteke et al. ( 25 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Rohrer et al. ( 26 ) | Y | Y | Y | UC | N | Y | Y | Y | Include |
| Jäger et al. ( 27 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Al-Khateeb et al. ( 28 ) | Y | Y | Y | Y | UC | Y | UC | Y | Include |
| Takamatsu et al. ( 29 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Bot et al. ( 30 ) | Y | Y | Y | Y | Y | UC | Y | Y | Include |
| Cordes et al. ( 31 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Lima et al. ( 32 ) | Y | UC | Y | Y | Y | Y | Y | Y | Include |
| Toyozawa et al. ( 33 ) | Y | N | Y | Y | Y | Y | Y | Y | Include |
| Kaur et al. ( 34 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Katakura et al. ( 35 ) | Y | Y | Y | Y | UC | N | Y | Y | Include |
| Tonk et al. ( 36 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Kuroda and Nakagawa ( 37 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
| Kanawaka et al. ( 38 ) | Y | Y | Y | Y | Y | Y | Y | Y | Include |
2.4. Data extraction
Endnote® version 7 (Clarivate Analytics) was used to screen and extract data from the selected studies. Two researchers extracted data based on standard criteria, first based on the title and if not clear or in case of discrepancy, abstracts were searched. The chosen articles were reviewed by the remaining author. The extracted data were then used to complete the population, intervention, comparison, and outcome (PICO) table and analyzed for further information (e.g., proposed mechanisms and reported management).
2.5. Quality of the studies
The methodological quality of case report studies was evaluated using the Joanna Briggs Institute (JBI) critical appraisal checklist ( 13 ). This checklist comprises eight Likert questions that assess crucial aspects of case reports. These included the accurate presentation of patient demographic information, proper documentation of patient history, a comprehensive description of the current clinical conditions of patients, clear expression of diagnostic measures, thorough presentation of therapeutic measures, elucidation of patients' conditions post-therapeutic interventions, and identification and explanation of the causes of reported side effects. The assessment also encompassed an evaluation of the overall utility of the case reports, as detailed in Table 1 .
3. RESULTS
A search in the mentioned databases, conducted up to March 25, 2024, resulted in 204 articles being selected, of which 108 duplicates were removed, leaving 96 articles that were independently examined by two researchers. Screening of titles and abstracts led to the removal of 60 more articles. Finally, the remaining articles were examined in full text, which resulted in the exclusion of 5 articles due to intervention method, language, type of drug, and adverse effect ( Fig. 1 ). One article was added after the search was updated on May 5, 2025. Lastly, 32 articles were considered eligible, and the clinical details of 40 patients were recorded. The related studies were summarized in Table 2 . Fourteen studies were published from the United States, followed by 7 studies recorded from Japanese patients, and the rest were conducted in European countries (France, Germany, Belgium, Switzerland, UK, etc. ). Accordingly, 40 patients from 32 studies on 9 MAbs as monotherapy and 2 combination therapies were identified. Among the 40 patients, 13 were female, 23 were male, and the sex of the remaining patients was not reported.
Table 2
Case reports of aseptic meningitis induced by anti-cancer monoclonal antibodies.
3.1. MAbs causing AM
3.1.1. Cetuximab
Cetuximab, a MAb, inhibits the dimerization of the epidermal growth factor receptor (EGFR), thereby preventing the activation of downstream signaling pathways that promote tumor proliferation and survival ( 42 ). Some of the adverse effects of this drug include skin rashes, infusion reactions, gastrointestinal disorders, and headache ( 43 ). Although research on different neurological adverse effects of cetuximab has been limited, cases of seizure, polyneuropathy, headache, confusion, and delirium have been reported ( 44 ).
AM is a rare neurological adverse effect of cetuximab, which occurs in head and neck malignancies, and most commonly after the first dose. Symptoms are typical and last for a few days. Cerebrospinal fluid (CSF) shows increased white blood cell (WBC) count, elevated neutrophil proportion, and increased protein levels, which typically return to normal within a few days. Management has been documented with corticosteroids, empiric antibiotics, rechallenge with lower doses, heavier premedication, and slower infusion rate ( 43 ).
As shown in Table 2 , cetuximab was the most reported suspect of reviewed case reports on AM. Of the fourteen patients in this group, 8 were male, 9 had head and neck malignancies, and 13 had received the first dose.
3.1.2. Rituximab
Rituximab is a chimeric MAb targeting CD20, used in the treatment of various conditions, including non-Hodgkin's lymphoma, rheumatoid arthritis, and CLL ( 45 ). Rituximab has some adverse effects, such as late-onset neutropenia, immune reconstitution defects, infections, progressive multifocal leukoencephalopathy, reactivation of hepatitis, intestinal perforation, and interstitial pneumonitis ( 46 ). In addition, rare neurological adverse effects of rituximab include seizure, cerebral infarction, and serotonin syndrome ( 47 ). Also, AM has been reported in patients with systemic lupus erythematosus and hypogammaglobulinemia secondary to rituximab ( 48 ).
During the review of literature, we encountered one case report of using this MAb as part of chemotherapy.
3.1.3. Ipilimumab
Ipilimumab, a MAb that targets the immune-inhibitory molecule CTLA-4, has shown promise in the treatment of advanced melanoma, with potential applications in prostate and non-small cell lung cancers ( 49 ). These include potentially fatal conditions such as enterocolitis and ileitis, as well as less severe but still significant cutaneous effects ( 50 , 51 , 52 , 53 ). Some of the neurological adverse effects linked to ipilimumab therapy include inflammatory myopathy, AM, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myasthenia gravis-like syndrome, sensorimotor neuropathy, and inflammatory enteric neuropathy ( 30 , 53 ).
The data presented in Table 2 reveal that melanoma was the most common malignancy type in patients, and it happened seemingly regardless of dose and time of administration. Six patients in 5 researches were evaluated. CSF analysis showed a rise in lymphocyte count, and patients were responsive to corticosteroid administration.
3.1.4. Nivolumab
Nivolumab, a programmed cell death protein 1 (PD-1) blocking antibody, has shown promising results in the treatment of advanced and metastatic renal cell carcinoma. It has also been used for unresectable malignant melanoma ( 54 ). Nivolumab adverse effects include rare events like adrenal insufficiency and autoimmune diabetes. Common side effects are pneumonitis, thyroiditis, hepatitis, pruritus, vitiligo, and diarrhea ( 54 ). Rare but potentially severe neurological adverse effects linked to nivolumab include inflammatory myopathy, AM, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome, myasthenia gravis-like syndrome, and neuropathy ( 55 ).
Literature review revealed three reports of AM. All exhibited rose lymphocyte in CSF analysis. One was re-challenged without return of symptoms, and methylprednisolone was described as effective in its management.
3.1.5. Ipilimumab + nivolumab
The combination of ipilimumab and nivolumab is a first-line treatment for metastatic renal cell carcinoma ( 56 ). It has shown efficacy in patients with advanced melanoma and hepatocellular carcinoma receiving the combination of ipilimumab and nivolumab ( 57 , 58 ).
Ipilimumab and nivolumab combination has been associated with a higher risk of adverse effects than ipilimumab or nivolumab monotherapy. Common side effects include fatigue, diarrhea, pruritus, rash, and gastrointestinal disorders such as colitis and enterocolitis ( 59 , 60 ). In addition, there are some serious neurological side effects, such as myasthenia gravis, encephalitis, and toxic encephalopathy, in the administration of the combination ( 53 ).
The literature review results showed that the ipilimumab and nivolumab combination-induced AM was diagnosed in five patients from four studies. As expected, WBC counts presented in CSF rose supporting inflammatory mediation, and patients responded well to prednisolone therapy.
3.1.6. Pembrolizumab
Pembrolizumab is a PD-1 blocking antibody used in cancer immunotherapy to treat various types of cancer, such as non-small cell lung cancer ( 61 ). Pembrolizumab has serious adverse effects, including acute renal failure, severe neurological toxicity, myopathy, psychosis, and lichen planus. Also, the neurological immune-related adverse events include myasthenia gravis, encephalitis, myositis, and acute inflammatory demyelinating polyradiculoneuropathy ( 62 ).
Two patients, males of 67 and 55 years old, were recorded as having AM related to this medicine. CSF involvement, non-time dependence, and response to steroids were reported ( Table 2 ).
3.1.7. Daratumumab
Daratumumab targets CD38, inducing apoptosis in CD38 + multiple myeloma cells. It is generally well tolerated, but hematological reactions such as neutropenia, anemia, and thrombocytopenia are reported ( 63 ). Leukoencephalopathy has been reported as a neurological adverse effect of daratumumab ( 64 ).
3.1.8. Atezolizumab
Atezolizumab targets programmed death ligand 1 (PD-L1), enhancing T-cell activity against tumor cells by blocking the PD-L1/PD-1 immune checkpoint ( 65 ). Side effects with this drug range from autoimmune diabetes, encephalitis, and hemolytic anemia to gastrointestinal disorders ( 66 ). The neurological side effects include encephalitis, meningoencephalitis, neuropathy, acute inflammatory demyelinating polyneuropathy, ataxia, seizure, and myopathy ( 67 ).
3.1.9. Apolizumab
Apolizumab targets the HLA-DR β-chain on B cells, inducing complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and apoptosis of B cells ( 68 ). The neurological side effects, including global aphasia, seizure, motor weakness, diffuse cerebral edema, and coma, have been reported with this drug ( 69 ). According to the literature review results, apolizumab was detected in the patient’s CSF ( Table 2 ).
3.1.10. Alemtuzumab
Alemtuzumab, targeting CD52, is utilized in treating lymphoid malignancies like CLL and T-cell prolymphocytic leukemia ( 70 ). Alemtuzumab can increase the risk of stroke, both ischemic and hemorrhagic, as well as autoimmune-related secondary disorders such as Guillain-Barré syndrome ( 71 ).
4. DISCUSSION
This research aimed to investigate the underlying mechanisms of AM in patients undergoing chemotherapy with MAbs. The study sought to identify the at-risk patient population and to develop personalized treatment strategies that can improve the safety and efficacy of MAbs used in malignancy treatments.
AM of cetuximab has been expressed in many cases, and the mechanism behind this phenomenon has been hypothesized as immune-mediated against the drug molecule or a direct effect of the drug in meninges ( 21 , 26 , 27 ).
Intravenous immunoglobulin (IVIG) associated with AM is stated in many publications ( 21 , 72 , 73 ). It has been suggested that IgG crossing the blood-brain barrier (BBB) induces an inflammatory reaction in the meninges ( 33 ). Speculation of BBB cross of cetuximab has been shaded by its large molecule structure, although Prasanna et al. stated that EGFR inhibitors may result in the release of proinflammatory cytokines, which could potentially disrupt the BBB and allow entry into the CSF ( 19 ). Based on Maritaz’s research , the release of histamine, serotonin, and prostaglandin as a result of inflammatory reaction could lead to meningeal microvasculature ( 21 ). Kaur et al. proposed that hypersensitivity reaction with steroid response, as other mechanism can empower this hypothesis ( 34 ). Chung et al. stated that an IgE-mediated reaction due to infusion of cetuximab can be another possible mechanism, and, as seen in some re-challenged cases, slow infusion and premedication with H 1 and H 2 antihistamines didn’t lead to reappearance of symptoms ( 74 ). Dose-dependency has been suggested as a risk factor behind this side effect as high doses of cetuximab are administered in the first dose ( 27 ). However, in colorectal cancer, one of the most prevalent cancers, cetuximab is administered in high doses, and more frequently, many fewer reports have been recorded in colorectal cancer patients. Though in some reports, authors suggested that occurrence might not be dose-dependent and irrespective of dose, the first exposure to cetuximab may cause irritation of the meninges ( 18 ). Also, the half-life of cetuximab aligns with the onset and alleviation of symptoms. Premedication with glucocorticoid is effective in some cases after re-challenge ( 27 ). Inflammatory reaction of this drug has been connected to its chimeric structure, as panitumumab, a humanized MAb with the same mechanism, has not been reported causative of AM, thus changing to this agent has been used as a management in some cases reported ( 27 ). As most of the patients affected were suffering from head and neck malignancy may suggest a specific inflammatory mechanism. Interleukin-6 has been proposed to be involved in processes of squamous cell carcinomas of the head and neck associated with tumors. Therefore, it is conceivable that cytokine activation may be linked to cetuximab-associated AM ( 27 ).
The exact mechanism behind pembrolizumab-induced AM is not fully understood. However, it is believed to be related to the immunological response triggered by the immune checkpoint inhibitor ( 24 , 32 ). Steroids have been suggested as a management option, affecting the duration of response to immunotherapy ( 32 ).
The occurrence of ipilimumab-induced meningitis may be linked to the attraction of the drug to the cranial nervous system. It is believed that ipilimumab frequently triggers hypophysitis, an ailment thought to be caused by the expression of CTLA-4 in the anterior pituitary cells and resulting in a type II hypersensitivity reaction ( 12 , 57 ). The potential involvement of a T helper 1 (Th1)/Th17-mediated autoimmune response may have been raised, as evidenced by the elevated presence of Th1 phenotype lymphocytes and a notable proportion of Th17 phenotype in the CSF ( 22 ). Immune-related adverse events (irAEs) with ipilimumab are prevalent in 14-77% of patients, apparently a high incidence since the action of this drug leads to T-cell proliferation and activation, which may respond to autoantigens ( 30 ).
The concurrent administration of anti-PD-1 and anti-CTLA-4 antibodies in combination therapy is anticipated to demonstrate a heightened efficacy. Nevertheless, it is noted that the incidence and intensity of irAEs may surpass therapy with each individual ( 35 ). If patients experience ipilimumab-induced irAEs, prompt steroid treatment can help to reduce the severity and duration of symptoms, even in cases where steroids are usually ineffective, such as Guillain-Barré syndrome or hypophysitis. Severity and frequency of irAEs appear to be dose-dependent, although immunotherapeutic do not show a dose-response in a linear curve manner as they depend on the immune system of the host to induce a response ( 38 ). Emerging evidence has established a relationship between irAEs and the effectiveness of immune checkpoint inhibitors (ICIs) in individuals diagnosed with solid tumors ( 31 ). According to a prior report, although steroid therapy was not effective, natalizumab, which inhibits lymphocytes from entering the BBB, was successful in treating autoimmune encephalitis as an irAE, which was triggered by the combination of ipilimumab and nivolumab ( 56 ).
Notably, the exact mechanism of nivolumab-induced AM is not fully elucidated. The mechanism of nivolumab-induced AM involves irAEs and is similar to other ICIs. These adverse effects are believed to be predominantly mediated by T cells, with some cases potentially involving other immune cells. In the context of immune-mediated encephalitis related to ICIs, antibodies against N-methyl-D-aspartate (NMDA) receptors have been implicated in the pathogenesis. These antibodies, found in patients with immune-mediated encephalitis, may cross-react with NMDA receptors in the brain, leading to encephalitis ( 75 ). Al-Khateeb et al. stated one possible explanation that is the suppression of an immune response targeting antigens common to both tumor and non-malignant tissues, potentially resulting in self-directed immunity ( 28 ). Additional research indicated that agents targeting CTLA-4 may induce the reduction of regulatory T-cells, influencing their function in inhibiting cell-mediated immune responses. Furthermore, it has been suggested that regulatory T-cells upregulate PDL1/PDL2 in the tumor microenvironment. The involvement of B-cells in the pathophysiology is also considered significant ( 76 ). Mizukami et al . reported that the concentration of interleukin-6 is proportional to the magnitude of the manifestation of meningoencephalitis ( 77 ).
The mechanism of rituximab-induced AM involves the impact of the drug on B cells and subsequent immune response. Rituximab leads to B cell depletion and hypogammaglobulinemia. This depletion affects the humoral immune response, potentially predisposing individuals to severe infections like AM caused by enteroviruses ( 17 ). Thus, IVIG seems a plausible treatment option used in the reported case.
The postulated mechanism behind daratumumab-induced AM involves immune hypersensitivity responses, likely related to T-cells, leading to meningeal inflammation ( 23 ).
Despite an extensive search of the literature, there was no specific mechanism related to alemtuzumab-induced AM. Nevertheless, it is notable that alemtuzumab can be involved in depleting lymphocytes, immune reconstitution syndrome, which can result in irAEs. The alemtuzumab effects seem to be dose-independent. The patients receiving the reduced doses of alemtuzumab revealed similar adverse immune - related events, whereas the high doses used in multiple sclerosis have not been reported to induce the same effects ( 41 ).
Japanese patients are believed to be more predisposed to atezolizumab-induced irAEs. Approximately 12% of Japanese cancer patients treated with atezolizumab displayed meningitis. Though the exact mechanism of this phenomenon is not explained, as atezolizumab is considered an ICI, the same mechanism explained for other members of this category can be proposed for atezolizumab ( 33 ).
There were some limitations in this study. Case reports and case series were frequently considered weak sources of evidence due to the high risk of bias. Also, language limitations hindered us from reviewing some of the articles.
5. CONCLUSION
AM is considered one of the bothersome complications of drug therapy. The emergence of new MAbs raises significant long-term safety concerns. Post-marketing surveillance reports of MAbs pose new challenges regarding the management of symptoms and replacement of offending agents. This study aimed to review and evaluate the published reports on cancer treatment and MAbs-associated AM to shed light on new insights and assist fellow healthcare providers in better managing patients and improving quality of life.
Conflict of interest statement
The authors declared no conflict of interest in this study.
Authors’ contributions
S. Emami contributed to the concept, design, and definition of the intellectual content; F. Nasr Esfahani performed the literature search; N. Ghalandari carried out data analysis and prepared the manuscript; S. Ataei was responsible for manuscript editing and review.
All authors have read and approved the finalized article. Each author has fulfilled the authorship criteria and affirmed that this article represents honest and original work.
AI declaration
During the preparation of this work, the authors used ChatGPT 4.0 to improve the text grammatically, readability, and language, but the drafting, idea structure, and data collection were carried out without any help from this tool. After using this tool, the authors reviewed and edited the content and take full responsibility for the content of the publication.
Acknowledgements
Authors like to thank the Vice Chancellor of Research at Hamadan University of Medical Sciences.
6. REFERENCES
1. 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. DOI: 10.4103/1735-5362.367793.
2. 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. DOI: 10.1001/jamaneurol.2017.1912.
3. 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. DOI: 10.4103/1735-5362.367791.
4. 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. DOI: 10.1136/annrheumdi s-2012-202293.
5. 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. DOI: 10.4103/RPS.RPS_28_23.
6. 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. DOI: 10.1016/j.ejca.2016.12.001.
7. 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. DOI: 10.1056/NEJMoa1003466.
8. 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. DOI: 10.1056/NEJMoa1507643.
9. 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. DOI: 10.1056/NEJMoa1412082.
10. 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. DOI: 10.1016/S1470-2045(15)00083-2.
11. 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/j co.2011.29.15_suppl.e16033.
12. 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. DOI: 10.1097/CJI.0b013e318156e47e.
13. 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. DOI: 10.11124/JBISRIR-D-19-00099.
14. 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.
15. Feinstein TM, Gibson MK, Argiris A. Cetuximab-induced aseptic meningitis. Ann Oncol. 2009;20(9):1609–1610. doi: 10.1093/annonc/mdp382. DOI: 10.1093/annonc/mdp382.
16. Nagovskiy N, Agarwal M, Allerton J. Cetuximab-induced aseptic meningitis. J Thorac Oncol. 2010;5(5):751,1–1. doi: 10.1097/JTO.0b013e3181d408bc. DOI: 10.1097/JTO.0b013e3181d408bc.
17. 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.
18. Emani MK, Zaiden RA. Aseptic meningitis: a rare side effect of cetuximab therapy. J Oncol Pharm Pract. 2013;19(2):178–180. doi: 10.1177/1078155212447973. DOI: 10.1177/1078155212447973.
19. 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. DOI: 10.1136/bcr-2015-209622.
20. 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. DOI: 10.1016/j.jocn.2014.11.034.
21. 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. DOI: 10.1186/s12885-016-2434-7.
22. 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. DOI: 10.1684/ejd.2016.2943.
23. 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. DOI: 10.1016/j.clml.2018.05.018.
24. 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. DOI: 10.3892/mco.2022.2553.
25. 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.
26. 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. DOI: 10.1177/1078155217739685.
27. Jager 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. DOI: 10.1159/000527075.
28. 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. DOI: 10.1136/bcr-2023-258141.
29. 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. DOI: 10.3892/mco.2019.1929.
30. 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. DOI: 10.1136/practneurol-2012-000447.
31. 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. DOI: 10.1002/ccr3.2534.
32. 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. DOI: 10.1155/2019/7183747.
33. 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. DOI: 10.1016/j.jtocrr.2020.100012.
34. 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.
35. 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. DOI: 10.3389/fendo.2021.722586.
36. 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. DOI: 10.1016/j.ejca.2019.08.004.
37. 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. DOI: 10.1002/rcr2.1076.
38. 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. DOI: 10.1159/000535476.
39. 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. DOI: 10.1093/annonc/mdw558.
40. 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. DOI: 10.3109/10428190903186486.
41. 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. DOI: 10.1111/ejh.13204.
42. 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. DOI: 10.2174/157489208784638776.
43. 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.
44. 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.
45. Tridente G. 1th. Milano: Springer; 2013. Adverse Events with Biomedicines: prevention through understanding; pp. 351–368. DOI: 10.1007/978-88-470-5313-7.
46. 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. DOI: 10.1080/10428190902934944.
47. 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.
48. 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. DOI: 10.1186/s12883-018-1102-8.
49. Cameron F, Whiteside G, Perry C. Ipilimumab: first global approval. Drugs. 2011;71(8):1093–1104. doi: 10.2165/11594010-000000000-00000. DOI: 10.2165/11594010-000000000-00000.
50. Witges K, Shafer LA, Zarychanski R, Abou-Setta AM, Rabbani R, Dingwall O, et al. Ipilimumab-induced enterocolitis: a systematic review and metaanalysis. Drug Saf. 2020;43(12):1255–1266. doi: 10.1007/s40264-020-00979-4. DOI: 10.1007/s40264-020-00979-4.
51. 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. DOI: 10.1186/s12885-015-1074-7.
52. 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. DOI: 10.1684/ejd.2017.3023.
53. 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.
54. 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. DOI: 10.7759/cureus.22070.
55. 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. DOI: 10.1186/s40425-018-0421-z.
56. 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. DOI: 10.1002/cam4.6306.
57. 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. DOI: 10.1158/2767-9764.CRC-23-0072.
58. 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. DOI: 10.3389/fonc.2023.1187840.
59. 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. DOI: 10.1177/17588359211058393.
60. 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. DOI: 10.3389/fonc.2022.877434.
61. 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.
62. 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. DOI: 10.3389/fphar.2022.774170.
63. Raedler LA. Darzalex (daratumumab): first anti-CD38 monoclonal antibody approved for patients with relapsed multiple myeloma. Am Health Drug Benefits. 2016;9:70–73. (Spec Feature) PMID: 27668047.
64. 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. DOI: 10.2147/OTT.S365657.
65. 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. DOI: 10.1358/dot.2017.53.4.2589163.
66. 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. DOI: 10.1177/2050313X18792422.
67. 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. DOI: 10.1159/000526248.
68. Fracasso PM, Goodner SA, Wildi JD, Naughton MJ, Linette GP, Govindan R, et al. A phase I study of apolizumab, an anti-HLA-DR β-chain monoclonal antibody, in patients with solid tumor malignancies. Am J Clin Oncol. 2022;45(7):294–297. doi: 10.1097/COC.0000000000000924. DOI: 10.1097/COC.0000000000000924.
69. 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. DOI: 10.3390/curroncol30060440.
70. 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. DOI: 10.1038/sj.onc.1210380.
71. 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. DOI: 10.1053/j.seminoncol.2006.01.027.
72. 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. DOI: 10.7326/0003-4819-121-4-199408150-00004.
73. Hamrock DJ. Adverse events associated with intravenous immunoglobulin therapy. Int Immunopharmacol. 2006;6(4):535–542. doi: 10.1016/j.intimp.2005.11.015. DOI: 10.1016/j.intimp.2005.11.015.
74. 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. DOI: 10.1056/NEJMoa074943.
75. 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. DOI: 10.1371/journal.pone.0053745.
76. 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. DOI: 10.1186/s13256-018-1786-9.
77. 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. DOI: 10.1620/tjem.2022.J071.