Predictive short/long-term efficacy biomarkers and resistance mechanisms of CD19-directed CAR-T immunotherapy in relapsed/refractory B-cell lymphomas

Abstract

Genetically modified T-cell immunotherapies are revolutionizing the therapeutic options for hematological malignancies, especially those of B-cell origin. Impressive efficacies of CD19-directed chimeric antigen receptor (CAR)-T therapy have been reported in refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL) patients who were resistant to current standard therapies, with a complete remission (CR) rate of approximately 50%. At the same time, problems of resistance and relapse following CAR-T therapy have drawn growing attention. Recently, great efforts have been made to determine various factors that are connected to the responses and outcomes following CAR-T therapy, which may not only allow us to recognize those with a higher likelihood of responding and who could benefit most from the therapy but also identify those with a high risk of resistance and relapse and to whom further appropriate treatment should be administered following CAR-T therapy. Thus, we concentrate on the biomarkers that can predict responses and outcomes after CD19-directed CAR-T immunotherapy. Furthermore, the mechanisms that may lead to treatment failure are also discussed in this review.

Are we ready for personalizedCAR‐Ttherapy?

“…CAR‐T therapy remains a relatively novel treatment option and attempts to improve its efficacy are the subject of numerous studies 2,5–8 . The poor prognosis after its unsuccessful use mainly relates to patients with advanced disease stage, to those with severe irreversible adverse reactions, and in a group with impaired T cells.…”

“…CAR‐T cells' greater precision in attacking specific cancer cells may significantly reduce the risk of damaging healthy ones, thereby improving their efficiency. Moreover, of significance are methods which improve longevity and proliferative ability of cells 2,3 . Another problem concerns patients who were ineligible for CAR‐T therapy due to failure in T‐cells collection or their further modification, the solution to which could become allogeneic (allo) CAR‐T cells 4 .…”