CAR-T Cell Therapy: Firing Up the Engines as a Possible B-Cell Directed Treatment for MS

Jeffrey Cohen, MD

(Credit: Cleveland Clinic)

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of some cancers, especially leukemias and lymphomas. But does it offer similar promise in multiple sclerosis (MS)?

CMSC annual meeting speaker Jeffrey Cohen, MD, Director of the Experimental Therapeutics Program in Cleveland Clinic’s Mellen Center for Multiple Sclerosis, focused much of his Whitaker lecture on the better-researched stem-cell approaches. CAR-T is the new kid on the block, he said, and one of the other cellular therapies to watch along with regulatory T-cell (T-reg) transplantation.

How Does CAR-T Cell Therapy Work?

CAR-T cells are engineered effector T-cells that have a chimeric antigen receptor, usually derived from antibodies and coupled to an intracellular activation domain. This allows for antigen-specific killing off of cellular targets. In CAR-T therapy, usually a 1-time event, the patient's white blood cells are collected via leukapheresis. After the patient’s T-cells are activated, they are engineered to the antigen receptor, usually using a viral vector. Those cells are then expanded in culture and reinfused after the patient has completed a course of chemotherapy. This chemotherapy regimen, usually comprising cyclophosphamide and fludarabine, is much less intense than that involved in stem cell transplantation, Cohen said.

Status Of CAR-T Cell Therapy In MS Research

CAR-T approaches targeted for MS are directed against CD19, which leads to the depletion of B cells similar to the currently available anti-CD20 monoclonal antibodies, Cohen explained. A number of anti-CD19 CAR-T therapies are approved to treat B-cell–derived malignancies, notably lymphoma. A few case reports are available in patients with MS, but clinical trials in MS are just beginning to ramp up. A phase 1 study now underway is looking at 2 patient populations with MS: one with highly active relapsing disease and a second group with nonactive progressive MS.

“We're still trying to decide the best target population and work out the relative risks and benefits,” Cohen said. “We don't know the appropriate CAR-T dose in MS or whether to use the patient's own CAR-T cells or an allogeneic product.”

Safety Concerns with CAR-T Therapy

Clinical trials should help shed light on the feasibility of CAR-T cell treatment in MS, but the safety considerations cannot be ignored, Cohen said. Acute safety issues include mild reactions to leukapheresis or chemotherapy, but more severe potential adverse events include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome, or ICANS. CRS results from the release of pro-inflammatory mediators at the CAR-T activation stage.

Symptoms can include fever, fatigue, anorexia, and headache, ranging in severity from mild to even life-threatening when organ failure is involved. ICANS is essentially CRS combined with encephalopathy. Treatments include antipyretics, corticosteroids, and IL-6 blockade using tocilizumab. Certain factors can provide clues to which patients are at higher risk.

Potential long-term safety issues also exist, most of them relatively modest, Cohen added. These include hypogammaglobulinemia, infection, B-cell aplasia, and the potential for hematologic toxicities. In oncology settings, secondary T-cell–derived malignancies and secondary autoimmune conditions have been observed.

Rationale for Pursuing CAR-T Research in MS

“Since they both kill B cells within the blood, why would someone pursue CAR-T instead of using B-cell directed monoclonal antibodies?” Cohen noted. “The main advantage of CAR-T is a much deeper B-cell depletion within the tissues, including the central nervous system. The hypothesis is that this may better address some of the immunopathology in MS.”

T-cell therapy is expensive, he added, and somewhat more risky than treatment with B-cell depleting monoclonal antibodies, but some of this is balanced out against the potential for needing just a single treatment, and therefore less long-term risk.