Clinical Update: Dosing Underway in Trial of First CRISPR-Engineered Switchable Allogeneic CAR-T Candidate

AvenCell Therapeutics recently announced that the first patient has been dosed in a Phase 1A study with its lead product candidate AVC-201. This novel allogeneic switchable CAR-T candidate targets CD123 and is being developed for the treatment of relapsed or refractory acute myeloid leukaemia and other CD123-associated blood cancers.

By: Karen O'Hanlon Cohrt - Mar. 6, 2024
News

In a recent press release, CAR-T therapy startup AvenCell Therapeutics announced that it has dosed the first patient in its Phase 1A clinical trial of AVC-201, which is the company's lead clinical allogeneic cell therapy programme.

AVC-201 is a CD123-targeting 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. It is engineered to fully avoid rejection by both the innate and adaptive host immune system.

A universal switchable CAR-T platform - how does AVC-201 work?

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.

First patient dosed in AVC-201 trial

The AVC-201 Phase 1 study is expected to include up to 37 patients, and it will be conducted at multiple sites in Germany and the Netherlands. The primary objective of the trial is to assess the safety profile of AVC-201 and to determine the maximum tolerated dose. Secondary measures will include efficacy, safety, and CAR-T persistence.

AvenCell, which was launched in 2021 by Blackstone Life Sciences, Cellex Cell Professionals and Intellia Therapeutics, is building a pipeline of autologous and allogeneic cell therapies that are engineered to persist as long as possible, and developing a universal and switchable construct that allows complete control and target redirection of T cells after their infusion into a patient.

According to its website, AvenCell is leveraging Intellia Therapeutics' proprietary allogeneic platform based on CRISPR-Cas9 gene editing to overcome the immunological challenges associated with allogeneic cell therapies, and it has been granted a license to combine Intellia’s CRISPR-Cas9 allogeneic platform with AvenCell’s universal, switchable CAR T-cell platforms. The in-licensed approach applies a novel combination of edits to generate persistent allogeneic T cell products for better anti-tumour efficacy. These edits include: knock-out of the endogenous T-cell receptor to prevent graft-versus-host disease, and knock-out of HLA class II expression in combination with knock-out of an HLA class I protein allow allogeneic T cells to escape recognition by host T and NK cells.

The EMA approved AvenCell's clinical trial application for AVC-201 in July 2023.

Read the full press release published by AvenCell Therapeutics here.

For a complete overview of CRISPR IND approvals and ongoing gene-editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.

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News: Clinical Update: Dosing Underway in Trial of First CRISPR-Engineered Switchable Allogeneic CAR-T Candidate
News: Clinical Update: Dosing Underway in Trial of First CRISPR-Engineered Switchable Allogeneic CAR-T Candidate
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