The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.

Immune-mediated protection generated to COVID-19 mRNA vaccines is associated with anti-Spike (S) protein neutralizing antibodies. However, humoral immunity is compromised in B cell depleting (BCD) therapies, used to treat autoimmune diseases such as Multiple Sclerosis (MS). To study the effect of BCD on the durability and protective efficacy of vaccine-induced immunity, we evaluated S-reactive antibodies and T cell responses 1–70 weeks post-vaccination in MS cohorts treated with BCD compared to non-BCD therapies from four centers. BCD-treated participants had significantly reduced antibody levels and enhanced frequencies of S-reactive CD4⁺ and CD8⁺ memory T cells to COVID-19 vaccination compared to the non-BCD group, with some variations among different BCD formulations. T cell memory responses persisted up to 14 months post-vaccination in both BCD and non-BCD cohorts, who experienced similar clinical protection from COVID-19. Together, our results establish a critical role for T cell-mediated immunity in anti-viral protection independent of humoral immunity.

ICANS is a common form of neurological immunotoxicity from CAR T-cell therapy (CAR-T). While high tumor burden, product type and cell dose are established risk factors, there are many unknowns. Our objective was to characterize novel neurological and non-neurological risk factors for the development of ICANS in subjects who received CAR-T. We retrospectively identified 93 subjects (60% men, mean age 60) who had undergone CD19 or BCMA-targeting CAR-T for hematological malignancy from 2018 to 2023 at a large academic hospital. Incidence of ICANS was 31.2%, high-grade in 9.7%. A low baseline MOCA score (p=0.008) was associated with ICANS when controlled for baseline ferritin, KPS, and age; loss of points on specific cognitive sub-scores was also significant, with poor attention testing of particular concern. Presence of preexisting cerebrovascular disease, active autoimmune disease, and neurological tumor involvement were not associated with increased risk. ICANS was also associated with older age (p=0.024), elevated baseline ferritin (p=0.006), low KPS (p=0.004), and preceding or concurrent CRS of any grade (<0.001). Increasing ferritin between baseline and Day 5+ (p=0.002) was associated with development of high-grade ICANS, along with prior tocilizumab exposure (p=0.015). Subjects who developed any grade of ICANS had higher 90-day mortality than those who did not (p<0.001). Identification of these additional baseline risk factors for ICANS will help identify high-risk patients ahead of treatment and allow for improved preventative planning and early identification of ICANS. Key Points Low baseline MOCA score is an independent risk factor for ICANS. Impaired baseline attention testing is of particular concern. Baseline cerebrovascular disease, neurological exam focality, and active autoimmune disease are not associated with ICANS.