Abstract
I
The use of autologous lentivirus-transduced anti-CD19 CAR–T cells has been previously demonstrated to have potential antitumor effects in B cell–derived malignancies. 2 Patients like Layla, however, whose endogenous T cell populations are depleted, are not suitable candidates for autologous lentivirus-transduced CAR–T cell therapy. The Cellectis product uses donor T cells that have been engineered with TALENs to inactivate the expression of both endogenous T cell receptors and CD52, the latter rendering the cells insensitive to the lymphodepleting agent alemtuzumab, before introducing the anti-CD19 CAR. These gene-edited CAR–T cells can then exert antitumor effects, while avoiding the graft-versus-host disease that would otherwise result from an allogeneic T cell response against host tissues. This double modification requires the genome-editing strategy that is provided by TALEN.
At the time of this editorial, data from the first human subject have not yet been presented in detail, nor have they undergone peer review. Thus, it is difficult to draw any scientific conclusions as to the safety or efficacy of this product. Nonetheless, this event represents an important milestone in the human use of genome editing. The fact that this has occurred in the context of one of the most promising new approaches to cancer immunotherapy seems particularly propitious. The promise of allogeneic anti-CD19 CAR–T therapy for B cell cancers stems not only from its ability to provide hope for patients like Layla, but also from the fact that a single donor source of CAR–T cells could potentially be much more readily scaled up for broader clinical use. This latest announcement highlights how rapidly clinical progress in human gene therapy is advancing.