CAR T Cell–Associated CRS, Neurotoxicity

Chimeric antigen receptor (CAR) T-cell therapy is an exciting, rapidly progressing field in cancer immunology. During clinical trials, CAR T-cell therapy has shown unprecedented efficacy in the management of hematological malignancies and produced sustained tumor regressions in a majority of treated patients.^1,2

CAR T and other adoptive cell therapies work by harnessing and boosting the natural capacity of the immune system to fight cancer.² The technology used for this therapy involves genetically engineering T cells to express recombinant CARs that recognize specific antigens on the surface of cancer cells.

With antigen recognition on cancer cell surfaces, targeted and specific T-cell–mediated cytotoxicity is then triggered independent of major histocompatibility complex (MHC).^2,3 This allows CAR T cells to overcome mechanisms of immune escape used by cancer cells, such as downregulation of MHC molecules. In addition to selective destruction of tumor cells, the natural development of CAR T memory cells allows for durable and sustained antitumor immunity, preventing tumor recurrence.²

CAR T-cell technology was born in the late 1980s, with the first design of chimeric T-cell receptors in 1989.^2,4 Since then, several key discoveries were made to improve CAR T persistence, cytotoxicity, and resistance to tumor-induced immunosuppression and overcome manufacturing challenges.²

In 2017, the FDA approved the first 2 CAR T products: axicabtagene ciloleucel (Yescarta; Kite Pharma) and tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) for the treatment of patients with relapsed or refractory leukemia and lymphoma. Brexucabtagene autoleucel (Tecartus; Kite Pharma) CAR T-cell therapy was approved by the FDA for adult patients with relapsed or refractory mantle cell lymphoma in July 2020. Most recently, in March 2021, idecabtagene vicleucel (Abecma; Bristol Myers Squibb) was approved for the treatment of relapsed or refractory multiple myeloma.

CAR T-cell therapy can cause potentially serious adverse events (AEs), including cytokine release syndrome (CRS) and neurotoxicity, ranging in severity from mild to life-threatening.⁵ The incidence and onset of CRS varied in clinical trials, with the incidence ranging from 35% to 100% and onset from 1 to 63 days depending on CAR construct, diagnosis, and various CRS grading systems.^6-8 The symptoms may include high-grade fevers, myalgias, arthralgias, and rigors, whereas more severe, life-threatening manifestations include hypotension, vascular leak, cytopenias, coagulopathy, and multiorgan failure.^1,5,6 Pathogenesis of CRS is thought to be associated with a high level of inflammatory cytokines released by the CAR T cells, other immune cells, and lysed target cells.^5,6

During clinical trials, neurotoxicity was reported in up to 67% of patients; however, the incidence varied widely depending on the product, patient factors, and the grading scale used in the studies.^5,7 Neurologic symptoms were most commonly observed as occurring within 1 to 3 weeks after CAR T-cell infusion, although delayed presentation has been reported.^6,7 The pathophysiology of neurotoxicity is linked to the high systemic concentrations of inflammatory cytokines affecting blood-brain barrier (BBB) permeability and infiltration of T cells into the central nervous system (CNS).⁶

Treatment algorithms for CRS and neurotoxicity vary depending on different CAR T-cell products and trials.⁶ Supportive care, evaluation to exclude other etiologies, and administration of antibiotics are recommended for mild CRS. Agents used to attenuate the immune response associated with CAR T-cell expansion include corticosteroids and cytokine-targeted therapies such as tocilizumab (Actemra; Genentech USA), siltuximab (Sylvant; EUSA Pharma), and anakinra (Kineret; Sobi).^5-7

Because corticosteroids may theoretically adversely affect the efficacy of CAR T cells, tocilizumab, an anti–IL-6 receptor monoclonal antibody (mAb) approved by the FDA for the treatment of CAR T-cell therapy–associated CRS, is commonly the first choice after appropriate supportive care. However, neurologic toxicity has been observed with tocilizumab; this is hypothesized to be caused by the biochemical upsurges in IL-6 levels and inability of tocilizumab to cross BBB.^5,7

Unlike tocilizumab, anti–IL-6 mAb siltuximab binds IL-6 directly and prevents binding of this inflammatory cytokine to soluble and membrane-bound receptors in the peripheral circulation, as well as in the CNS. Therefore, it is used in both the treatment of CRS resistant to first-line therapy and neurotoxicity; however, data supporting its use in neurotoxicity remain limited.

Another cytokine-targeted agent is the IL-1 receptor antagonist anakinra, which is used in treatment of refractory CRS and, with limited data, neurotoxicity as well. Supportive care and high-dose corticosteroids are the first-line treatment recommendations for CAR T cell–associated neurotoxicity, with seizure prophylaxis also recommended. Use of defibrotide is being investigated in this setting and as a potential addition to treatment with siltuximab and anakinra.

CAR T therapy has revolutionized cancer treatment options, and ongoing research promises to solve many challenges associated with this technology.^1,2,9 For example, research efforts are working to make great strides in strategies to improve CAR T therapy efficacy and safety, as well as investigate novel CAR T-cell designs used in the treatment of cancers other than hematological malignancies, such as solid tumors.

Alina Varabyeva, PharmD, is the clinical pharmacy specialist—leukemia service at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Jordan Pleskow, PharmD, is the clinical pharmacy specialist— transplant and cellular therapy service at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

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