Introducing controllable switches could improve the safety profile of CAR-T therapy

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Researchers show the feasibility of using a doxycycline inducible controllable switch to regulate CAR-T cell activity, to increase the safety profile of CAR-T therapy. Toxicity associated with CAR-T therapy is a major concern for advancing this therapy to solid tumors and other diseases.

Chimeric antigen receptor T (CAR-T) cell therapy has produced astonishing results in clinical trials, resulting in the approval of Kymriah and Yescarta for treating B-cell malignancies. However, the safety issues associated with CARs in the form of off-tumor effects pose a major challenge to advancing this field. Researchers around the world are actively working on developing strategies to program control into CAR-T cells, to make the therapy safer.

In the present study published in PLoS One, Dr Tuna Mutis and team of VU University Medical Center (The Netherlands), have developed a strategy to control CAR-T cell activity to increase its safety profile.

Using the multiple myeloma-associated CD38 molecule as target molecule, the team tested the feasibility and utility of a doxycycline (DOX) inducible Tet-on inducible CD38-CAR design to control the off-target cytotoxic activity of CAR-T cells.

To do this, they first generated a Tet-on inducible second generation CD38-CAR. Upon retroviral transduction of T cells with the inducible CAR, the cells showed no detectable CAR expression in the absence of DOX but expressed high levels of the CAR within 48 hours of exposure to high doses of DOX. The expression and activity levels of the CAR were also shown to be directly regulated by the DOX dose used. When 10ng/ml DOX dose was used, its removal resulted in a relatively rapid decay of CAR- related off-tumor effects within 24 hours, indicating the active controllability of undesired CAR activity.

Taken together, these results indicate the possibility to utilize such a DOX inducible Tet-on CAR-design to actively regulate the CAR-mediated activities of therapeutic T cells. Development of such controllable switches, the team believes, would lead to safer application of CAR-T cell therapy.

Source: Drent E et al., Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design. PLoS One May 2018. DOI