Creating Personalized Immunotherapy in Large B-Cell Lymphoma

When the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel) works in large B-cell lymphoma (LBCL), the results can seem miraculous. But this expensive treatment does not work for about a quarter of patients who receive it, and researchers who presented results at the recent annual meeting of the American Society of Hematology (ASH) think they know why.

In CAR T-cell therapy, a patient’s T cells are removed and engineered in a manufacturing process to express a receptor that will target and kill cancer kills. These CAR T cells are then reinfused back into the patient, and it is typically clear within a month whether the treatment has worked.

Researchers led by Robbie G. Majzner, MD, of Stanford University School of Medicine wanted to find out what went wrong when CAR T-cell therapy did take hold. They analyzed genetic samples from 51 patients who received axi-cel and learned that 25% of the patients had tumors that lacked a functioning version of the protein CD58. In all but 1 of these patients, the treatment did not produce lasting effects.

The researchers then confirmed their findings in a mouse model that lacked CD58; the team tested 3 different CAR T therapies in the mice, but none worked.

Are patients whose tumors lack CD58 out of luck? Perhaps not. The research team determined that CD58 helped activate the biological mechanisms that allowed the CAR T-cell therapy to kill cancer. So, the researchers added a different protein, CD2, the T-cell ligand for CD58, to the job of the missing protein.

CD2, the researchers wrote in their abstract, “plays both an adhesive role and a costimulatory role in T cells.” In a series of experiments, they noted that blocking CD2 greatly reduced cytokine production after CAR stimulation, but this can be a sign the treatment is not working.

Conversely, by modifying CAR T cells with the additional protein, the researchers were able to show in additional experiments with mice that the treatment can work without CD58. This approach could be tested in clinical trials within the next 2 years.

The results would be of interest to payers, who have tried to create CAR T payment structures that reimburse drug makers only when the treatment works. However, there are many significant administrative costs for the institutions that must be absorbed somewhere, and this has created access issues for patients without commercial coverage.

“Achieving an uptick of 20% to 25% in the complete response rate would really bring cures to a large number of additional patients,” Majzner said in a statement. “Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy.”

Reference

Majzner RG, Frank MJ, Mount C, et al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 558.