CRS associated with CAR T cells, neurotoxicity

Chimeric antigen receptor (CAR) T cell therapy is an exciting and rapidly advancing area in cancer immunology. In clinical trials, CAR T cell therapy has shown unprecedented efficacy in the management of hematologic malignancies and produced sustained tumor regressions in the majority of patients treated.1.2

CAR T and other adoptive cell therapies work by harnessing and enhancing the immune system’s natural ability to fight cancer.2 The technology used for this therapy involves the genetic engineering of T cells to express recombinant CARs that recognize specific antigens on the surface of cancer cells.

With the recognition of the antigen on the surface of cancer cells, targeted and specific cytotoxicity mediated by T cells is then triggered independent of the major histocompatibility complex (MHC).2.3 This allows CAR T cells to overcome immune escape mechanisms used by cancer cells, such as downregulating MHC molecules. In addition to the selective destruction of tumor cells, the natural development of CAR T memory cells enables long-lasting and sustained anti-tumor 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 have been made to improve the persistence, cytotoxicity, and resistance of CAR T 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, the idecabtagene vicleucel (Abecma; Bristol Myers Squibb) has been 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 fatal.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 the CAR construct, diagnosis and various classification systems of CRS.6-8 Symptoms can include high-grade fevers, myalgia, arthralgia, and chills, while more serious and life-threatening manifestations include hypotension, vascular leakage, cytopenias, coagulopathy, and multiple organ failure.1.5.6 The pathogenesis of CRS is believed to be associated with an elevated level of inflammatory cytokines released by CAR T cells, other immune cells, and lysed target cells.5.6

In clinical trials, neurotoxicity has been reported in up to 67% of patients; however, the incidence varied considerably depending on the product, patient factors and the rating scale used in the studies.5.7 Neurologic symptoms were most commonly seen within 1 to 3 weeks of CAR T cell infusion, although delayed presentation has been reported.6.7 The pathophysiology of neurotoxicity is related to elevated systemic concentrations of inflammatory cytokines affecting blood brain barrier (BBB) ​​permeability and T cell infiltration into the central nervous system (CNS).6

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

Since corticosteroids can theoretically interfere with the efficacy of CAR T cells, tocilizumab, an anti-IL-6 receptor monoclonal antibody (mAb) approved by the FDA for the treatment of CRS in combination with cell therapy CAR, is usually the first choice after appropriate supportive care. However, neurological toxicity has been observed with tocilizumab; this is thought to be caused by biochemical increases in IL-6 levels and the inability of tocilizumab to cross BBB.5.7

Unlike tocilizumab, the anti-IL-6 mAb siltuximab binds directly to IL-6 and prevents the binding of this inflammatory cytokine to soluble and membrane 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 remains limited.

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

CAR T therapy has revolutionized cancer treatment options, and current research promises to solve many of the challenges associated with this technology.1,2,9 For example, research efforts aim to make great strides in strategies to improve the efficacy and safety of CAR T therapy, as well as to study new designs of CAR T cells used in the treatment of other cancers. as malignant blood diseases, such as solid tumors.

Alina Varabyeva, PharmD, is the Clinical Pharmacy Specialist in the Leukemia Department at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Jordan Pleskow, PharmD, is the Clinical Pharmacy Specialist in the Transplantation and Cell Therapy Department at Roswell Park Comprehensive Cancer Center in Buffalo, New York.


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