UMGCCC Researchers Pioneer Triple CAR T-Cell Therapy, Conduct First-in-Human Trial

In December 2023, a research team led by Djordje Atanackovic, MD, Professor of Medicine at University of Maryland School of Medicine, Director of Cancer Immunotherapy and Medical Director of the Fannie Angelos Cellular Therapeutics GMP Laboratory at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC), submitted a new clinical study to the U.S. Food and Drug Administration (FDA). This world-leading study, developed by UMGCCC's team in conjunction with a biopharmaceutical industry partner, represents the first test of trispecific CAR T-cell therapy for recurrent or difficult-to-treat B-cell lymphomas.

This trial, A Phase 1a Study of LT2950 Trispecific CAR T-Cells for Patients with Relapsed/Refractory B-Cell Lymphomas, is the first time trispecific CAR T-cells will be studied in humans. Moving quickly because of the project's immense promise, the FDA approved the UMGCCC team to move forward in January 2024. The team is currently enrolling patients who have relapsed or refractory B-cell lymphomas and hopes to enroll a total of 15 individuals in the study. Three other academic medical centers nationwide have joined the University of Maryland in this trial.

"It's the first time we are submitting a clinical study where we are making the CAR T-cells locally, in our facility," Dr. Atanackovic said. UMGCCC researchers worked closely with Miltenyi, a Gaithersburg, MD-based pharmaceutical company, to jointly develop the idea. The team has produced the clinical-grade CAR T-cell products locally, in the Fannie Angelos lab.

CAR T therapy modifies a patient's own white blood cells to attack and destroy cancer cells by recognizing a specific antigen on the cancer cell's surface. All current CAR T-cell therapies available target the same antigen, CD19, and CAR T-cell therapy is typically very effective in treating B-cell lymphomas. The problem is, in about 50 percent of cases, the cancer returns.

The cancer cells evade the remaining CAR T-cells in the patient's blood by mutating, dropping the specific targeted antigen (CD19) from their surface. This renders the cancer cells invisible to the CAR T-cells, invalidating their ability to recognize and kill the cancer cells.

In contrast, trispecific CAR T-cells (also called "triple CAR T-cells") simultaneously target three B-cell leukemia and lymphoma antigens. Dr. Atanackovic and his team believe that the use of trispecific CAR T-cells is a promising strategy to prevent the downregulation of target antigen and subsequent antigen loss-mediated relapse in patients with B cell malignancies.

"We're hoping that this will prevent antigen loss-mediated relapse," Dr. Atanackovic said.

The trispecific CAR-T cells the UMGCCC team has developed with Miltenyi target three antigens at the same time (CD19, CD20, and CD22). These three antigens are the most broadly expressed in B-cell lymphomas, so researchers expect this approach to be effective in the majority of B-cell malignancies. Even in patients who have received previous single-target CAR T-cell therapy and had a relapse, researchers expect CD20 and/or CD22 to be expressed in the new, mutated cancer cells.

"This study will serve as a proof of principle," Dr. Atanackovic noted. "These are the first trispecific CAR T-cells. So, if this works for B-cell lymphoma, if by including three targets versus just one, we can prevent relapses or treat patients who have already had a relapse, then we could do the same thing for other diseases as well."

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