Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells

Abstract

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient’s outcome when compared with <7 days of steroids. Management of CAR T cell–mediated neurotoxicity warrants evaluation in prospective clinical trials.

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

“…Tocilizumab has since been FDA approved for treatment of CAR T cell-induced life-threatening CRS [40]. Neurological toxicities have been reported following CAR T cell infusion as well; however, preventative approaches remain elusive [36,[41][42][43][44]. Compared to CRS and neurotoxicity, a much more manageable consequence of CAR T cell therapy targeting B cell malignancies is the resulting B cell aplasia.…”

Seizures in patients with cancer

“…Of the therapies listed in Table , we highlight chimeric antigen receptor T‐cell therapies because these are increasingly being used for the treatment of refractory acute lymphocytic leukemia and lymphoma; and their neurotoxicity, most commonly characterized clinically by aphasia and encephalopathy, is frequently accompanied by EEG abnormalities (generalized periodic discharges) and seizures …”

“…Of the therapies listed in Table 1, we highlight chimeric antigen receptor T-cell therapies because these are increasingly being used for the treatment of refractory acute lymphocytic leukemia and lymphoma; and their neurotoxicity, most commonly characterized clinically by aphasia and encephalopathy, is frequently accompanied by EEG abnormalities (generalized periodic discharges) and seizures. [3][4][5] Infections and metabolic derangements are other impo rtant causes of seizures in patients with cancer. Treatment-related immunosuppression puts patients who have cancer at increased risk of central nervous system infection with less common pathogens (Cryptococcus, human herpes virus 6).…”

Advances in CAR T Therapy for Hematologic Malignancies

“…Most cases of ICANS are reversible within 4 weeks of symptom onset. [95][96][97][98] Neurotoxicity following CAR T was initially graded using CTCAE 20 with criteria most appropriate for antibody rather than cellular therapies (infusion interruption impacted grading) until a CAR T specific assessment tool, the CARTOX-10 87 was proposed. Minor modifications to the CARTOX-10 resulted in the immune effector cell-associated encephalopathy (ICE) assessment tool (Table 3), incorporated in the ASTCT ICANS consensus grading scale for adults (Table 4).…”

“…97 Animal models have demonstrated the importance of macrophage-derived IL-1 which were abolished by anakinra without impacting CAR T persistence. 76 Patient and therapy risk factors for ICANS include a prior history of neurologic comorbidity, 95,97 higher marrow disease burden, 96 higher CAR T expansion 96 or dose, 97 fludarabine LDC, 97 and thrombocytopenia prior to CAR T, 98 some of which are shared with CRS. The extent of ferritin elevation during ICANS correlates with severity of neurotoxicity.…”