Penn Medicine’s ‘Armored’ CAR-T Cell Therapy Shows Early Success Against Relapsed/Refractory B-Cell Lymphoma

Penn Medicine in Philadelphia has announced positive results from a phase 1 study of a next-generation CAR-T cell therapy in patients with relapsed or refractory B-cell lymphomas who have gone through several rounds of cancer treatments, including currently available CAR-T cell therapies.

CAR-T cell therapy is a type of immunotherapy that uses genetically modified T cells to target and destroy cancer cells. The process of producing CAR-T cell therapies begins with collecting blood from a patient (autologous) or donor (allogeneic) and isolating the T cells. These T cells are then sent out to a laboratory, where they are engineered to express chimeric antigen receptors (CARs) on their surfaces. Treatments designed to treat B-cell-mediated lymphomas and leukemias typically target the antigen CD19 found on B-cell surfaces.

The enhanced T cells are then multiplied to produce millions of cells and infused back into the patient. The full process can take about 9 to 14 days.

The first CAR-T cell therapy was developed by Carl June, M.D., the Richard W. Vague Professor in Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania and approved by the FDA in 2017 to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Since then, six additional CAR-T cell therapies have been introduced to the market. Four of the seven are approved for B-cell lymphomas.

Although these revolutionary therapies have transformed blood cancer treatment, they are not a magic bullet. While many patients experience complete remission and long-term survival after receiving CAR-T cell therapy, not all patients respond to the treatment. In fact, 30% to 60% of patients treated with CD19-directed CAR-T cell therapy eventually relapse.

Because CAR-T cell therapy is reserved for patients who have already undergone multiple cancer treatments, the prognosis is poor and options are few for those who relapse after receiving CAR-T cells.

To address this challenge, June and his research team at Penn Medicine developed an enhanced “armored” form of CAR-T cell therapy called huCART19-IL18 for now. Like its predecessors, huCART19-IL18 targets CD19. However, the new generation investigational product is further modified to release the proinflammatory cytokine interleukin 18 (IL-18). IL-18 can enhance the immune system and potentially support the engineered T cells by recruiting other immune cells that protect the CAR-T cells and promote cancer cell destruction.

The phase 1 study enrolled 21 patients with relapsed or refractory B-cell lymphomas who had received a median of seven other cancer treatments. Twenty of the participants had tried CAR-T cell therapy. Each patient received huCART19-IL18 treatment. A total of 52% of patients experienced complete remission, and 81% saw improvement in their cancer.

The study results were published today in the New England Journal of Medicine.

“Based on these results, we believe that incorporating cytokine secretion into CAR-T cell design will have broad implications for enhancing cellular therapies, even beyond blood cancers,” June said in a press release. “With longer T cell persistence and expansion, this strategy could be powerful in settings where CAR-T hasn’t performed as well, such as solid tumors,” he added.

Penn’s Center for Cellular Immunotherapies has also developed a process that shortens the production process for the CAR-T cells to three days versus the standard 9 to 14 days.