European Clinical Trial Approved for First CRISPR-Engineered Switchable Allogeneic CAR-T Candidate

AvenCell Therapeutics, a CAR-T therapy startup launched by Blackstone Life Sciences, Cellex Cell Professionals and Intellia Therapeutics, recently announced that the European Medicines Agency (EMA) has approved its clinical trial application for AVC-201, a novel CRISPR-edited allogeneic therapy for the treatment of various blood cancers.

AVC-201, the company's lead clinical allogeneic cell therapy programme, is a CD123-directed switchable CAR-T candidate designed to target and eliminate cells that express the receptor CD123, including relapsed or refractory acute myeloid leukaemia and several other blood cancers.

The candidate, which is being developed as an off-the-shelf treatment for eligible cancers, leverages AvenCell's UniCAR universal/switchable technology, which allows for therapeutic activity to be switched on and off. AVC-201 is also developed using in-licensed allogeneic cell engineering technology developed by Intellia Therapeutics, which allows for unrelated donors to provide cells for patients.

Universal switchable CAR-T platform

AVC-201 is the first CRISPR-engineered CAR-T candidate to be developed with a regulatable on/-off switch.

The switch is provided by AvenCells' Universal Targeting platform, a controllable CAR-T cell technology that can turn CAR-T cells “OFF” and “ON” by means of separately infused soluble adaptors called Targeting Modules (TMs). The cells are further edited with CRISPR-Cas9 technology to avoid graft-versus-host disease and host immune rejection.

Here's how it works: donor-derived T cells are transduced to express a biologically-inert universal CAR against tumour antigens. A TM, which is infused separately to the CAR-T cells, comprises a flexible antigen-binding moiety, which is linked to a motif recognised by the universal CAR. Thus, the TM provides antigen specificity to the CAR-T cells, redirecting and activating them to act on the target, which in this case is CD123. The presence or absence of the TM in circulation elegantly allows “on” and “off” control, respectively, of the therapeutic activity.

A switchable CD-123-targeting CAR-T candidate is designed to solve the problem of on-target off-tumour toxicity seen with conventional CD123-targeting strategies, and thus offer an improved therapeutic window for clinical application.

The development of AVC-201 builds upon promising clinical data demonstrating success of the switchable platform in AvenCells' autologous AVC-101 programme, which is currently being evaluated in a Phase 1 trial.