Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Abstract

Patients with B-cell hematologic malignancies who progress through first- or second-line chemotherapy have a poor prognosis. Early clinical trials with autologous anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising results for patients who have relapsed or refractory disease. Lymphodepleting conditioning regimens, including cyclophosphamide, fludarabine, pentostatin, bendamustine, interleukin-2, and total body irradiation, are often administered before the infusion of CAR T cells, allowing for greater T-cell expansion. The major toxicity associated with CAR T-cell infusions is cytokine release syndrome (CRS), a potentially life-threatening systemic inflammatory disorder. The quick onset and progression of CRS require rapid detection and intervention to reduce treatment-related mortality. Management with tocilizumab can help ameliorate the symptoms of severe CRS, allowing steroids, which diminish the expansion and persistence of CAR T cells, to be reserved for tocilizumab-refractory patients. Other toxicities of CAR T-cell therapy include neutropenia and/or febrile neutropenia, infection, tumor lysis syndrome, neurotoxicity and nausea/vomiting. A review of patients' medications is imperative to eliminate medications that may contribute to treatment-related toxicities. Studies are ongoing to help optimize patient selection, preparation, safety, and management of individuals receiving CAR T cells. Long-term follow-up will help establish the place of CAR T cells in therapy.

A review of chimeric antigen receptor T-cells in lymphoma

“…Lower pretreatment disease burden prior to CAR-T infusion is shown to improve outcomes; however, studies using conditioning regimens that malignancy is known to be resistant to demonstrate improvement in peak CAR-T proliferation and persistence indicating that tumor debulking alone is unlikely to be the sole mechanism responsible for these results [18,20,54]. It is theorized that depletion of non-malignant lymphocytes improves access of CAR-T to proliferative cytokines as well as removing regulatory T lymphocytes that contribute to the immunosuppressive tumor microenvironment that is responsible for favorable outcomes [5,54]. IL-15, an endogenous cytokine known to encourage T-cell proliferation and function, is secreted in increasing amounts following administration of conditioning chemotherapy and higher area under the curve concentration of this cytokine is associated with higher peak CAR-T proliferation and induction of remission which further supports the use of conditioning chemotherapy prior to CAR-T infusion [26].…”

“…Given the overlap of clinical presentation of CRS and other common treatment related toxicities including sepsis, TLS, and DIC it is recommended that all patients undergo appropriate work up for these conditions and have early empiric administration of antibiotics in addition to supportive care with anti-pyretics, fluids, and vasopressors to combat avoidable morbidity and mortality. There are inconsistent reports of degree of CRS correlating with improved outcomes and higher peak proliferation of CAR-Ts associated with increased CRS incidence; however, these observations remain of uncertain significance [5,18]. It has been consistently reported that high pretreatment disease burden is strongly associated with severity of CRS so pretreatment conditioning regimens are recommended as a way of mitigating CRS severity [17,19,20].…”

“…CAR-Ts are able to be constructed with specificity to any protein, carbohydrate, or glycolipid component to which a monoclonal antibody can be generated allowing profound versatility and non-ambiguity through localization to tumor antigens [3,4]. The receptor construct endows T cells with antibody type specificity for target antigen with major histocompatibility complex independent activation of a potent T-cell immune response to antigen-bearing tumor cells and is currently undergoing application to anti-tumor therapy in both hematologic and solid tumor malignancies [5,6].…”

“…The most commonly prescribed agents for treatment of CRS are Tocilizumab, a potent IL-6 receptor antibody, and corticosteroids. Tocilizumab administered intravenously over 1 h at 4-8 mg/kg (maximum of 800 mg/dose) with optional retreatment at 24-48 h with or without steroids is the preferred treatment for life threatening CRS [5,24]. The goal of assessment of CRS grade is to identify the well-defined group of patients who would benefit from early aggressive interventions while limiting compromise of treatment efficacy through excessive use of immunomodulatory therapy.…”

“…This score uses assessment of orientation, naming, ability to follow commands, writing, and attention to propose specific and objective discrimination of ICANS severity and administration of treatment [22]. Tocilizumab has poor CNS penetration so corticosteroids such as methylprednisolone administered at 2 mg/kg/day with rapid weaning or dexamethasone 0.5 mg/ kg at a maximum 10 mg are the preferred interventions for life threatening central nervous system manifestations of CAR-T toxicity [5,24].…”