She and her colleagues identified only 1 targeted study aimed at assessing cognitive impairments following ICI therapy: a pilot study based on 15 adults with cancer undergoing treatment with 1 of 3 ICI drugs.4 Based on cognitive tests, the authors had concluded that cognitive decline was linked to prior chemotherapy the patients had received and not the immunomodulators. However, Dr Joly and colleagues noted that the study’s small sample size — as well as the challenges in distinguishing the effects of 2 different lines of treatments and determining whether adverse events are even treatment-related reactions — make it impossible to draw any definitive conclusions from the research.

A 2017 preclinical study in mice offers deeper insight.5 In that research, investigators evaluated the effect of an anti–CTLA-4 antibody, administered alone or in combination with localized radiation, on the animals’ performance on behavior and cognition tests. While mice receiving both ICIs and radiation therapy saw the best control of tumor growth, cognitive and behavioral impairments in these animals were also observed. Senior author Jacob Reber, PhD, professor of behavioral neuroscience at Oregon Health and Science University’s school of medicine in Portland, attributed this to overactivation of the immune system following ICI therapy. “Chronic activation of the immune system might be bad for the brain,” he said.

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The mechanisms through which checkpoint inhibitors could impair cognitive function are unclear. In Dr Reber’s study, mice that received the ICIs, either alone or in combination with radiation, had heightened levels of proinflammatory cytokines in their blood. Some clinical research suggests that cytokines can cross the blood-brain barrier, possibly driving inflammation in the brain.

CAR-T therapies, which are currently approved to treat several hematological cancers, have been linked to severe toxicities. Approximately 37% to 93% of individuals with lymphoma undergoing therapy with CAR-T experience mild to severe cytokine release syndrome (CRS), which can affect any organ, including the nervous system.6 In addition, neurological toxicities — manifesting as encephalopathy, motor weaknesses, headaches, or seizures — have been reported to occur in 23% to 67% of patients with lymphoma undergoing CAR-T treatment.


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These toxicities could have implications for cognition, for instance, as a result of the massive release of cytokines that occurs during CRS. Elevated levels of cytokines have been identified in patients with B-cell acute lymphoblastic leukemia (ALL) who experienced severe neurotoxicities after being treated with CD19-directed CAR-T.3 The confirmation in 2015 of the presence of a central nervous system lymphatic system in the dural sinuses suggested that leukocytes — which would include engineered CAR-T cells — can penetrate the central nervous system directly and release cytokines there.7 

Other potential mechanisms exist, Dr Reber noted. Some chemotherapies have been suggested to potentially alter the permeability of the blood-brain barrier, and clinical studies of patients receiving chemotherapy followed by infusion of CAR-T cells revealed an enhanced permeability of the blood-brain barrier, which was demonstrated to impede the brain’s ability to protect itself from cytokines.8 In addition, immunotherapies or prior therapies could alter the gut microbiome, which could feasibly impact cognitive function, he added. 

In their report, Dr Joly and colleagues recommended that cognitive evaluations be performed in patients during and after the receipt of ICIs or CAR-T therapies to better understand the incidence of intellectual impairments in patients receiving immunotherapy. These analyses should be done in patients enrolled in immunotherapy clinical trials and in those who receive these therapies in real-world settings. The development of associated animal studies that investigate the mechanisms underlying these cognitive deficits is also warranted. 

Dr Reber agreed that more research is necessary. “There has to be treatment that works, but at the same time, we have to worry about the brain,” he said. As more patients receive immunotherapy treatments, “the more important it is that the quality of life of the patient is as high as it can be.” 

Disclosure: One of the coauthors of the primary review disclosed ties to the pharmaceutical industry. For a full list of disclosures, please refer to the original paper.

References

  1. Joly F, Castel H, Tron L, Lange M, Vardy J. Potential impact of immunotherapy agents on cognitive function in cancer patients [published online August 26, 2019]. J Natl Cancer Inst. doi: 10.1093/jnci/djz168
  2. Cuzzubbo S, Javeri F, Tissuer M, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:1-8.
  3. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol. 2017;30(6):659-668.
  4. Cuzzubbo S, Belin C, Chouahnia K et al. Assessing cognitive function in patients treated with immune checkpoint inhibitors: a feasibility study. Psychooncology. 2018;27(7):1861-1864.
  5. McGinnis GJ, Friedman D, Young KH et al. Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model. Oncotarget. 2017;8(6):9155-9173.
  6. Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The other side of CAR T-cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden. Am Soc Clin Oncol Educ Book. 2019;39:433-444.
  7. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337-341.
  8. Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404-1419.