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CAR T Cells
What You Need to Know About CAR T Cells

Released: February 04, 2016

Expiration: February 02, 2017

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Authors:  Jonathan Webster, MD, and B. Douglas Smith, MD

CAR T cell therapy is an important emerging therapy for many hematologic malignancies and has been in the news a lot recently. Here are the most important things you need to know about CAR T cells.

What Is a CAR T Cell?
CAR T cells are T cells taken directly from a patient that are then manipulated in the laboratory to target a specific antigen on a cancer cell and infused back into the patient to treat the existing malignancy. The most basic CAR is a synthetic, hybrid molecule comprising an antigen-binding domain derived from an antibody fused to a CD3ζ T-cell activation domain (Figure). Various methods have been used to introduce the CAR construct into T cells including retroviral or lentiviral vectors, electroporation, and transposon-based systems. Once the CAR has been introduced into the T cell, then the cells are selectively cultured to expand the desired population. This can yield effective CAR T cells in as few as 10 days and generates an adequate quantity of CAR T cells for infusion approximately 90% of the time.

Figure. Structure of a basic CAR.
 

How Do You Give CAR T Cells?
Creating and administering CAR T cells is a labor-intensive process that begins with leukapheresis to obtain patient lymphocytes. Leukapheresis can be performed at the time of disease relapse, following reinduction chemotherapy, or during a CR. The CAR construct is then introduced into the patient T cells as discussed above. The CAR T cells are then infused back to the patient as a primary treatment or following a chemotherapy-based preparative regimen. The need for a preparative chemotherapy regimen has been a subject of debate: some patients have achieved remission with no preparative regimen, while others have utilized cytotoxic regimens aimed at achieving disease control prior to CAR T cell infusion. Brentjens and colleagues demonstrated that lymphodepletion with cyclophosphamide led to improved persistence of CAR T cells, and thus lymphodepleting preparative regimens have been incorporated in most recent trials.

What Are the Current Applications of CAR T Cells?
The vast majorities of CAR T cell trials that are reported in the literature have focused on B-cell malignancies by targeting CD19, but a wide range of additional targets are being investigated. The first trials of CD19-targeted CAR T cells were primarily performed in non-Hodgkin lymphoma with early trials demonstrating limited efficacy but leading to significant improvements in the process of generating and administering CAR T cells. Savoldo and colleagues demonstrated that the addition of the costimulatory domain in second-generation CARs led to significantly increased expansion and persistence of CAR T cells following infusion. More recent studies including those by Kochenderfer and colleagues and Schuster and colleagues have included predominantly patients with relapsed or refractory DLBCL and demonstrated response rates of ≥ 50% across a spectrum of diseases with 57% of evaluable DLBCL patients achieving a CR in one study.

Efficacy results for CD19-targeted CAR T cells have been more impressive in ALL. Multiple trials, in both children/young adults and adults, have demonstrated CR rates of 70% to 90% with > 85% of the CR patients achieving an MRD-negative status in each of the trials. In many cases, the patients who have achieved remission have subsequently undergone an alloSCT without increased toxicity, and nearly all of these patients remain alive in CR. There are numerous patients who have maintained durable remissions (up to 24 months) without additional therapy, but many patients who have been ineligible for alloSCT have relapsed. Thus, CAR T cells cannot yet be considered definitive, curative therapy in ALL.

What Are the Adverse Events of CAR T Cells?
The 3 most significant adverse events of CAR T cells are cytokine release syndrome (CRS), neurologic toxicity, and B-cell aplasia. CRS occurs in the vast majority of patients who receive CAR T cells and, in its most severe form, is defined by fevers, hypotension, hypoxia, and neurologic disorders. Whereas CRS is mild for many patients, it can be severe in up to 25% of patients necessitating ICU admission and leading to median hospital stays of > 50 days. Multiple different cytokines have been identified as being involved in CRS, and potential clinical and lab markers are being explored to predict which patients treated with CAR T cells have the highest probability of severe CRS.

Common neurologic toxicities include seizures and delirium, which often occur simultaneously with CRS. The mechanism of neurologic toxicity remains unclear, although it is notable that similar events have been observed in patients treated with blinatumomab, a bichimeric antigen receptor engager that also targets CD19. Finally, B-cell aplasia is common in patients treated with CD19-targeted CAR T cells because B cells universally express CD19. Thus, B-cell aplasia has served as a useful pharmacodynamic marker in multiple studies.

How Are These Treatment-Related Symptoms Managed?
The neurologic toxicities and CRS seen with CD19-targeted CAR T cells are primarily managed with supportive care including antiepileptics for seizures, vasopressors for hypotension, and mechanical ventilation for hypoxia. Severe CRS was initially managed with high-dose steroids; however, this led to the rapid depletion of CAR T cells and disease relapse. Therefore, when studies demonstrated significant elevations in the inflammatory cytokine IL-6 in CRS, the IL-6 receptor antagonist tocilizumab was administered instead of steroids and led to improved CRS without depletion of CAR T cells. As B-cell aplasia leads to hypogammaglobulinemia, this is managed with IV immunoglobulins.

Where Is the Field Going?
Given the success of CAR T cells in ALL and to a lesser degree non-Hodgkin lymphoma, there is great enthusiasm for exploring novel targets for CAR T cells that will be applicable in other hematologic malignancies including Hodgkin lymphoma, multiple myeloma, and AML. Meanwhile, recent efforts have also focused on commercializing CAR T cells to move them outside of the handful of academic medical centers in the United States that currently have CAR T-cell programs.

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