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Neurologic Toxicities of Cancer Immunotherapies: a Review

  • Neuro-Oncology (P. Wen, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review provides clinical characterization and approach to management of neurotoxicities associated with checkpoint inhibitor therapy and chimeric antigen receptor T cell (CAR T cell) therapy.

Recent Findings

Immuno-oncology has revolutionized cancer treatment. The immunomodulatory effect of these treatments extends beyond the targeted cancers; however, with a range of immune-mediated toxicities being associated with these therapies. Both the peripheral and central nervous system are vulnerable to these toxicities, with several distinct clinical syndromes strongly associated with specific immunotherapies.

Summary

Neurologic immune-related adverse events are significant sequelae of both checkpoint inhibitors and CAR T cell therapy. In addition to clinical characterization of these syndromes, an understanding of the biologic underpinnings of these sequelae is essential. This will facilitate identification of patients at risk of these toxicities, develop treatments to prevent them and identify more effective clinical treatment when they occur.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Burnet M. Cancer; a biological approach. I. The processes of control. Br Med J. 1957;1(5022):779–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ehrlich P. Über den jetzigen Stand der Chemotherapie. Ber Dtsch Chem Ges. 1909;42(1):17–47.

    Article  CAS  Google Scholar 

  3. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.

    Article  CAS  PubMed  Google Scholar 

  4. 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):711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pan PC, Haggiagi A. Neurologic immune-related adverse events associated with immune checkpoint inhibition. Curr Oncol Rep. 2019;21(12):108.

    Article  PubMed  Google Scholar 

  6. Maeda O, Yokota K, Atsuta N, Katsuno M, Akiyama M, Ando Y. Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis. Nagoya J Med Sci. 2016;78(1):119–22.

    PubMed  PubMed Central  Google Scholar 

  7. Kyi C, Carvajal RD, Wolchok JD, Postow MA. Ipilimumab in patients with melanoma and autoimmune disease. J Immunother Cancer. 2014;2(1):35.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Merelli B, Massi D, Cattaneo L, Mandala M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol. 2014;89(1):140–65.

    Article  PubMed  Google Scholar 

  9. Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weiss MD, Luciano CA, Semino-Mora C, Dalakas MC, Quarles RH. Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma. Neurology. 1998;51(6):1738–41.

    Article  CAS  PubMed  Google Scholar 

  11. Tsuchida T, Saxton RE, Morton DL, Irie RF. Gangliosides of human melanoma. J Natl Cancer Inst. 1987;78(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  12. Gerdes LA, Held K, Beltran E, Berking C, Prinz JC, Junker A, et al. CTLA4 as immunological checkpoint in the development of multiple sclerosis. Ann Neurol. 2016;80(2):294–300.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sato K, Akamatsu H, Murakami E, Sasaki S, Kanai K, Hayata A, et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer (Amsterdam, Netherlands). 2018;115:71–4.

    Article  Google Scholar 

  14. Bomze D, Hasan Ali O, Bate A, Flatz L. Association between immune-related adverse events during anti-PD-1 therapy and tumor mutational burden. JAMA Oncol. 2019;5:1633.

    Article  PubMed Central  PubMed  Google Scholar 

  15. •• 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):1216–22 retrospective series evaluating the incidence of neurologic irAE.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer (Oxford, England : 1990). 2016;60:210–25.

    Article  CAS  Google Scholar 

  17. Lau KH, Kumar A, Yang IH, Nowak RJ. Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve. 2016;54(1):157–61.

    Article  PubMed  Google Scholar 

  18. Huh SY, Shin SH, Kim MK, Lee SY, Son KH, Shin HY. Emergence of myasthenia gravis with myositis in a patient treated with pembrolizumab for thymic cancer. J Clin Neurol (Seoul, Korea). 2018;14(1):115–7.

    Article  Google Scholar 

  19. Algaeed M, Mukharesh L, Heinzelmann M, Kaminski HJ. Pearls & Oy-sters: pembrolizumab-induced myasthenia gravis. Neurology. 2018;91(14):e1365–e7.

    Article  PubMed  Google Scholar 

  20. •• Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer (Oxford, England : 1990). 2017;82:128–36 early chearacterization of CPI-associated MG and its overlap with myositis.

    Article  CAS  Google Scholar 

  21. Kimura T, Fukushima S, Miyashita A, Aoi J, Jinnin M, Kosaka T, et al. Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci. 2016;107(7):1055–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Polat P, Donofrio PD. Myasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer. Muscle Nerve. 2016;54(3):507.

    Article  PubMed  Google Scholar 

  23. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet (London, England). 2018;391(10124):933.

    Article  Google Scholar 

  24. Suzuki S, Utsugisawa K, Yoshikawa H, Motomura M, Matsubara S, Yokoyama K, et al. Autoimmune targets of heart and skeletal muscles in myasthenia gravis. Arch Neurol. 2009;66(11):1334–8.

    Article  PubMed  Google Scholar 

  25. Tan RYC, Toh CK, Takano A. Continued response to one dose of nivolumab complicated by myasthenic crisis and myositis. J Thorac Oncol. 2017;12(7):e90–e1.

  26. •• Moreira A, Loquai C, Pfohler C, Kahler KC, Knauss S, Heppt MV, et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer (Oxford, England : 1990). 2019;106:12–23 systematic review of neuromuscular irAE from large registry.

    Article  CAS  Google Scholar 

  27. Cappelli LC, Gutierrez AK, Bingham CO 3rd, Shah AA. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res. 2017;69(11):1751–63.

    Article  Google Scholar 

  28. Sheik Ali S, Goddard AL, Luke JJ, Donahue H, Todd DJ, Werchniak A, et al. Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade. JAMA Dermatol. 2015;151(2):195–9.

    Article  PubMed  Google Scholar 

  29. Hunter G, Voll C, Robinson CA. Autoimmune inflammatory myopathy after treatment with ipilimumab. Can J Neurol Sci. 2009;36(4):518–20.

  30. Liewluck T, Kao JC, Mauermann ML. PD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies. J Immunother (Hagerstown, Md : 1997). 2018;41(4):208–11.

    CAS  Google Scholar 

  31. Fellner A, Makranz C, Lotem M, Bokstein F, Taliansky A, Rosenberg S, et al. Neurologic complications of immune checkpoint inhibitors. J Neuro-Oncol. 2018;137(3):601–9.

    Article  CAS  Google Scholar 

  32. Astaras C, de Micheli R, Moura B, Hundsberger T, Hottinger AF. Neurological adverse events associated with immune checkpoint inhibitors: diagnosis and management. Curr Neurol Neurosci Rep. 2018;18(1):3.

    Article  PubMed  CAS  Google Scholar 

  33. Thaipisuttikul I, Chapman P, Avila EK. Peripheral neuropathy associated with ipilimumab: a report of 2 cases. J Immunother (Hagerstown, Md : 1997). 2015;38(2):77–9.

    Google Scholar 

  34. Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barre syndrome in a melanoma patient. Ann Oncol. 2011;22(4):991–3.

  35. • Dubey D, David WS, Amato AA, Reynolds KL, Clement NF, Chute DF, et al. Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies. Neurology. 2019;93(11):e1093–e103 series of clinical cases of CPI-associated neuropathies.

    Article  CAS  PubMed  Google Scholar 

  36. Gao CA, Weber UM, Peixoto AJ, Weiss SA. Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma. J Immunother Cancer. 2019;7(1):262.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist. 2017;22(6):709–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Altman AL, Golub JS, Pensak ML, Samy RN. Bilateral facial palsy following ipilimumab infusion for melanoma. Otolaryngology--head and neck surgery : Otolaryngol Head Neck Surg. 2015;153(5):894–5.

  39. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460–7.

  40. Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13(4):278–80.

    Article  PubMed  Google Scholar 

  41. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol. 2017;30(6):659–68.

    Article  CAS  PubMed  Google Scholar 

  42. Schneider S, Potthast S, Komminoth P, Schwegler G, Bohm S. PD-1 checkpoint inhibitor associated autoimmune encephalitis. Case Rep Oncol. 2017;10(2):473–8.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lima G, Kahn A, Sama S, Savage J. Aseptic meningitis as an immune-related adverse event after pembrolizumab. Case Rep Oncol Med. 2019;2019:2.

    Google Scholar 

  44. Hottinger AF, de Micheli R, Guido V, Karampera A, Hagmann P, Du Pasquier R. Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. Neurol Neuroimmunol Neuroinflamm. 2018;5(2):e439.

  45. Chung M, Jaffer M, Verma N, Mokhtari S, Ramsakal A, Peguero E. Immune checkpoint inhibitor induced anti-glutamic acid decarboxylase 65 (anti-GAD 65) limbic encephalitis responsive to intravenous immunoglobulin and plasma exchange. J Neurol. 2020;267(4):1023–5.

  46. Williams TJ, Benavides DR, Patrice KA, Dalmau JO, de Avila AL, Le DT, et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 2016;73(8):928–33.

    Article  PubMed  Google Scholar 

  47. Wilson R, Menassa DA, Davies AJ, Michael S, Hester J, Kuker W, et al. Seronegative antibody-mediated neurology after immune checkpoint inhibitors. Ann Clin Transl Neurol. 2018;5(5):640–5.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neurooncol. 2014;16(4):589–93.

    CAS  Google Scholar 

  49. Zhang H, Watanabe R, Berry GJ, Vaglio A, Liao YJ, Warrington KJ, et al. Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A. 2017;114(6):E970–e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Daxini A, Cronin K, Sreih AG. Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clin Rheumatol. 2018;37(9):2579–84.

    Article  PubMed  Google Scholar 

  51. Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med. 2003;198(1):71–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Carter LL, Leach MW, Azoitei ML, Cui J, Pelker JW, Jussif J, et al. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2007;182(1–2):124–34.

    Article  CAS  PubMed  Google Scholar 

  53. Takizawa S, Kaneyama T, Tsugane S, Takeichi N, Yanagisawa S, Ichikawa M, et al. Role of the programmed death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease. J Neuroimmunol. 2014;274(1–2):78–85.

    Article  CAS  PubMed  Google Scholar 

  54. Gettings EJ, Hackett CT, Scott TF. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler (Houndmills, Basingstoke, England). 2015;21(5):670.

    Article  Google Scholar 

  55. Cao Y, Nylander A, Ramanan S, Goods BA, Ponath G, Zabad R, et al. CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology. 2016;86(16):1553–6.

    Article  PubMed  PubMed Central  Google Scholar 

  56. •• Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2(2):234–40 series evaluating CPI therapy in patients with pre-existing autoimmunity.

    Article  PubMed  Google Scholar 

  57. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361–5.

    Article  CAS  PubMed  Google Scholar 

  58. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. •• Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62 initial characterization and algorithmic approach to management of ICANS.

    Article  CAS  PubMed  Google Scholar 

  63. •• Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–38 Consensus guidelines on ICANS management.

    Article  CAS  PubMed  Google Scholar 

  64. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68.

    Article  CAS  PubMed  Google Scholar 

  65. Teachey DT, Bishop MR, Maloney DG, Grupp SA. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat Rev Clin Oncol. 2018;15(4):218.

    Article  PubMed  Google Scholar 

  66. Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Disco. 2017;7(12):1404–19.

    Article  CAS  Google Scholar 

  67. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Torre M, Solomon IH, Sutherland CL, Nikiforow S, DeAngelo DJ, Stone RM, et al. Neuropathology of a case with fatal CAR T-cell-associated cerebral edema. J Neuropathol Exp Neurol. 2018;77(10):877–82.

    Article  CAS  PubMed  Google Scholar 

  70. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science translational Med. 2014;6(224):224ra25.

    Article  CAS  Google Scholar 

  73. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Taraseviciute A, Tkachev V, Ponce R, Turtle CJ, Snyder JM, Liggitt HD, et al. Chimeric antigen receptor T cell-mediated neurotoxicity in nonhuman primates. Cancer Discov. 2018;8(6):750–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hu Y, Sun J, Wu Z, Yu J, Cui Q, Pu C, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol. 2016;9(1):70.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Ruark J, Mullane E, Cleary N, Cordeiro A, Bezerra ED, Wu V, et al. Patient-reported neuropsychiatric outcomes of long-term survivors after chimeric antigen receptor T cell therapy. Biol Blood Bone Marrow Transplantation. 2020;26(1):34–43.

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Rebecca A Harrison, Sudhakar Tummala and John de Groot each declare no potential conflicts of interest.

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Harrison, R.A., Tummala, S. & de Groot, J. Neurologic Toxicities of Cancer Immunotherapies: a Review. Curr Neurol Neurosci Rep 20, 27 (2020). https://doi.org/10.1007/s11910-020-01038-2

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