Dr Frank on Sequencing Questions With CAR22 in Relapsed/Refractory LBCL

Matthew J. Frank, MD, PhD, assistant professor, medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, lead investigator, clinical trials, Stanford Health Care, discusses remaining questions regarding treatment sequencing following preliminary results from a phase 1 trial (NCT04088890) of a CD22-directed CAR-T therapy (CAR22) in relapsed/refractory large B-cell lymphoma (LBCL).

At the 2023 EHA Congress, investigators shared data from a single-institution, phase 1 trial showing that a single infusion of CAR22 cells in this patient population (n = 38) elicited a best overall response rate of 68% and a complete response rate of 53%.

More research is needed to answer remaining sequencing questions, Frank begins. However, antigen loss remains a problem within this treatment landscape and inrecent trials, antigen levels were downregulated in patients whose disease relapsed, as well as in patients with low antigen levels or no expression of CD22, he explains. A way to address this unmet need may be to observe antigen levels, and identify whether a patient has CD19, CD20, or CD22 antigens, Frank adds. Notably, another area of interest to help address these questions is in the use of technology. Although current methods for detecting antigen levels, such as IHC, are limited, optimizingthese methods, by using flow-based methods, for instance, will increase the accuracy of measured antigen levels, he emphasizes.

Moreover, with the addition of emerging agents in this arena that target CD19 and CD20, investigators may want to use combinations, including triplets, Frank expands. It remains unknown whether using all agents in a single cell is more beneficial thanusing different cells. This question will have to be answered CAR by CAR, Frank notes. Sequential CARs will continue to be investigated in the future as well, as these have been shown to be feasible and effective, Frank explains.

Mechanisms of resistance, which are universal, will also continue to be investigated, Frank continues. Identifying CD58, which prevents CAR T-cells from being stimulated, will also be an area of interest, in addition to designing better CARs that don’t depend on CD58 signaling to activate, Frank concludes.