Details

Autor(en) / Beteiligte

• Richman, Sarah A.
• Wang, Liang-Chuan
• Moon, Edmund K.
• Khire, Uday R.
• Albelda, Steven M.
• Milone, Michael C.

Titel

Ligand-Induced Degradation of a CAR Permits Reversible Remote Control of CAR T Cell Activity In Vitro and In Vivo

Ist Teil von

• Molecular therapy, 2020-07, Vol.28 (7), p.1600-1613

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Chimeric antigen receptor (CAR)-modified T cells are endowed with novel antigen specificity and are most often administered to patients without an engineered mechanism to control the CAR T cells once infused. “Suicide switches” such as the small molecule-controlled, inducible caspase-9 (iCas9) system afford the ability to selectively eliminate engineered T cells; however, these approaches are designed for all-or-none, irreversible termination of an ongoing immune response. In order to permit reversible and adjustable modulation, we have created a CAR that is capable of on-demand downregulation by fusing the CAR to a previously developed ligand-induced degradation (LID) domain. Addition of a small molecule ligand triggers exposure of a cryptic degron within the LID domain, resulting in proteasomal degradation of the CAR-LID fusion protein and loss of CAR on the surface of T cells. This fusion construct allowed for reversible and “tunable” inhibition of CAR T cell activity in vitro. Delivery of the triggering molecule in CAR-LID-treated tumor-bearing mice temporarily reduced CAR activity through modulation of CAR surface expression. The ability to more flexibly modulate CAR T cell expression through a small molecule provides a platform for controlling possible adverse side effects, as well as preclinical investigations of CAR T cell biology. [Display omitted] To enable remote control over CAR T cell activity, Richman et al. incorporated a ligand-induced degradation (LID) domain into the CAR. This system created a reversible off switch, depending on the presence or absence of a small molecule ligand, permitting CAR T cell regulation in vitro and in vivo.