T cells attacking cancer cells

Chimeric antigen receptor (CAR)-modified T cells have become an important treatment option for some patients with hematologic malignancies, including non-Hodgkin lymphoma and acute leukemias. However, CAR T-cell treatment can be associated with cytokine release syndrome (CRS), which limits its utility by restricting administration only to experienced centers capable of managing this potentially fatal event. In a study recently published in Science Translational Medicine, Mestermann and colleagues report that the tyrosine kinase inhibitor dasatinib may serve as an effective “brake” for CAR T cells, enabling complete or partial inhibition of their activity on the basis of dasatinib dose. In in vitro and in vivo models, dasatinib was able to halt cytolytic activity, cytokine production, and proliferation of CAR T cells. This inhibition was rapidly cleared upon dasatinib discontinuation. When tested in a mouse model of CRS, a short treatment course of dasatinib administered after CAR T-cell infusion protected mice from CRS. The authors speculate that dasatinib could be used as a “rescue” medication to modulate the activity of CAR T cells in patients who experience severe CRS or other immune-mediated adverse events.

High Altitude: While this is an early, preclinical study that must be validated via clinical trial, it has far-reaching implications for researchers involved in CAR T-cell development One major limitation on the aggressiveness of CAR T-cell–based therapies has been the potential for immune-related toxicities such as CRS and the fear of losing control once the proverbial genie is out of the bottle. This study provides an important proof of concept that CAR T-cell activity can be regulated in a dose-dependent manner to provide a balance between anticancer effects and immune-related toxicity. Moving forward, agents such as dasatinib could be developed as potential “rescue” medications for severe toxicities with immunotherapies for cancer such as CAR T and bispecific antibody therapies. The availability of supportive therapies to possibly temper the activity of immunotherapies could open the door for development of potentially more-aggressive CAR T-cell technologies or to the reevaluation of CAR T approaches that were abandoned because of excessive immune-related toxicities.

Ground Level: The introduction of CAR T therapies has allowed some patients to experience long-term control of their disease, although outcomes have been less impressive in other settings (eg, multiple myeloma). CAR T-cell therapies are known to be associated with potentially severe side effects, which, combined with delays for the development of the cells and challenges in referral and reimbursements, can limit their utility. Indeed, many patients might not be referred because of the benefit:risk profile of CAR T therapies in patients with comorbidities. This article provides insight into one of the emerging methodologies to reduce the incidence of severe side effects and improve the safety of CAR T therapies. Although this approach is not yet ready for clinical practice, it does underscore the fact that the science of immunotherapy for cancer is continuously evolving. The relative benefit:risk ratios of the available therapies is not static, but rather must be reevaluated in the context of this changing environment.