Neurologic complications associated with CAR T-cell therapy

Introduction

Immune-based therapies have revolutionized cancer treatment. These agents enhance the immune system’s ability to seek out and attack tumor cells. One such treatment, CAR T-cells or chimeric antigen receptor T-cells, are a type of adoptive cell transfer therapy where a patient’s own T-cells are collected, genetically modified to treat their cancer, and reinfused. CAR T-cell therapy starts with collecting autologous T lymphocytes from a patient via leukapheresis. These cells are genetically engineered to express a modified T-cell receptor known as a chimeric antigen receptor (CAR), which binds to a specific cancer antigen such as CD19. Once CAR T-cells express the chimeric receptor of interest in vitro, they are expanded, purified, and infused back into the patient after the patient has received lymphodepleting chemotherapy. Once infused, cancer antigens stimulate the CAR T-cells to release cytotoxins, inducing cancer cell death, and resulting in treatment responses.

Structure, function, and administration of CAR T-cells

CARs are genetically engineered fusion proteins that redirect the specificity and function of T-cells. The CAR protein is composed of an extracellular antigen-recognition domain, a transmembrane domain, and an intracellular signaling module derived from T-cell signaling proteins. Each CAR contains the CD3ζ protein which plays a role in the activation of a T-cell.

• First-generation CARs contain CD3ζ

• Second-generation CARs possess a costimulatory endodomain (e.g., CD28 or 4-1BB) fused to CD3ζ

• Third-generation CARs consist of two costimulatory domains linked to CD3ζ

After a CAR construct is transfected into autologous or allogeneic peripheral blood T-cells using plasmid transfection, mRNA, or viral vector transduction, the T-cells are infused into the patient to target whichever surface-exposed tumor antigen is specified by the CAR’s extracellular targeting moiety, usually in the form of a single-chain variable fragment. Upon CAR engagement of its associated antigen, primary T-cell activation occurs and leads to cytokine release, cytolytic degranulation, and T-cell proliferation. Unlike vaccines and immunomodulatory agents that rely on in vivo priming of endogenous tumor-reactive cells and are therefore human leukocyte-antigen (HLA) restricted, CAR T-cells are capable of inducing durable antitumor responses in a universal, HLA-independent manner.

Leukapheresis . Leukapheresis is the first step in developing CAR T-cells for use in an individual patient. First, blood is removed from the patient, leukocytes are separated, and the remainder of the blood is returned to the circulation. After a sufficient number of leukocytes have been harvested, the leukapheresis product is enriched for T-cells. Next, the T-cells undergo an activation process during which they are incubated with the viral vector encoding the CAR, and after several days, the vector is washed out of the culture. Lentiviral vectors are used most frequently, but other methods of gene transfer are being explored. ^, When the cell expansion process is finished, the cell culture is concentrated to a volume that can be infused into the patient and is cryopreserved in infusible medium. Finally, when the product is released for treatment, the frozen cells are transported to the treatment site and thawed prior to administration. In patients with hematologic malignancies, lymphodepleting chemotherapy is typically administered prior to the CAR T-cell reinfusion. Lymphodepletion can substantially increase the in vivo expansion of the infused CAR T-cells by multiple effects, including reducing the patient’s lymphoid cell pool to make “space” for the CAR T-cells, increasing homeostatic cytokines, and ameliorating the tumor inhibitory microenvironment.

Efficacy and toxicity of CAR T-cell therapy

• Efficacy. The greatest advances for CAR T-cells have occurred in the treatment of hematologic malignancies, with the United States Food and Drug Administration (FDA) having approved two therapies as of the writing of this chapter. Tisagenlecleucel, a CD19-targeted CAR T-cell therapy formerly known as CTL019, was first approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Tisagenlecleucel was subsequently approved for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The second CAR T-cell therapy approved by the FDA was axicabtagene ciloleucel, which is also targeted against CD19 and is approved for adult patients with relapsed or refractory large B-cell lymphoma patients who have failed at least two prior therapies, including DLBCL, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Remarkably, both of these CAR products have led to durable remissions in patients with B-cell malignancies refractory to standard salvage therapies, with an overall response rate of 50–90% across multiple trials.

• Cytokine release syndrome. CAR T-cell therapies for hematologic malignancies have unique toxicities that are distinct from those of cytotoxic chemotherapy, small-molecule targeted therapies, and even from other immunotherapies. The most commonly observed toxicity with CAR T-cells is cytokine-release syndrome (CRS), which manifests as high fever, hypotension, hypoxia, and/or multiorgan toxicity. Rarely, cases of CRS progress to fulminant hemophagocytic lymphohistiocytosis (also known as macrophage-activation syndrome), which is characterized by severe immune activation, lymphohistiocytic tissue infiltration, and immune-mediated multisystem organ failure. ^, CRS is triggered by the activation of T-cells upon engagement of their CARs with cognate antigens expressed by tumor cells. When this occurs, both the activated T-cells, as well as bystander immune cells including monocytes and macrophages, release cytokines and chemokines that lead to a systemic inflammatory state that resembles sepsis physiology. CRS usually manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias, but can ultimately impact any organ in the body, including the heart, lungs, gut, liver, kidneys, bone marrow, or nervous system. CRS should be managed in accordance with the grade of this toxicity, which can be determined using established guidelines. Detailed discussion of the management of CRS is beyond the scope of this chapter, but interventions typically include supportive care such as intravenous fluid boluses, anti-interleukin (IL)-6 therapy with tocilizumab or siltuximab, and/or corticosteroids in cases refractory to anti-IL6 therapy.

In addition to ALL and DLBCL, CAR T-cells have shown promise in early phase trials in other hematologic malignancies, including multiple myeloma. ^, In solid tumors, however, response rates have been much less favorable. Some of the most significant challenges for CAR T-cell immunotherapy in solid cancers include (1) identification of unique tumor target antigens, (2) improved CAR T-cell trafficking to tumor sites, (3) addressing tumor heterogeneity and antigen loss, and (4) manipulating the immunosuppressive tumor microenvironment to allow for effective CAR T-cell expansion and tumor cell killing. While improved efficacy of CAR T-cells in solid tumors is eagerly awaited, patients enrolled on solid tumor CAR T-cell trials are at risk of many of the same complications as patients with hematologic malignancies. Thus, it is imperative that CRS and other compilations of CAR T-cells are recognized and managed appropriately by neurologists and other members of the care team. The remainder of this chapter will focus specifically on the neurotoxicity associated with CAR T-cell therapies.