Stealth CAR-Tregs: TRAC deletion for CD3 antibody evasion

bioRxiv France

Overview

Researchers have developed “Stealth” CAR-Tregs by deleting the T-cell receptor alpha chain (TRAC) to evade depletion by non-mitogenic CD3 antibodies. This strategy shifts the immune balance toward regulation by selectively eliminating activated T-cells while preserving CAR-Tregs, potentially reducing the cell dose required for clinical efficacy in organ transplantation.

In Depth

Key Findings

The study demonstrates that TRAC -/-CAR-Tregs exhibit robust protection from CD3 antibody-mediated depletion in circulation and peripheral tissues. In contrast, most TRAC +/+CAR-T cells are eliminated. Furthermore, the few TRAC +/+CAR-T cells that escape this depletion show a transcriptomic signature consistent with T-cell exhaustion, whereas TRAC -/-CAR-Tregs maintain their functional integrity.

Technical Details

The researchers utilized a combination of HLA-A2-targeted-CAR-Treg therapy and non-mitogenic CD3 antibody therapy to selectively deplete activated T-cells. The technical evaluation of TRAC deletion revealed the following:

• TRAC deletion does not impair antigen-specific activation or expansion of CAR-Tregs.
• The transcriptomic, phenotypic, epigenetic, and functional profiles of the cells remain unaffected by the deletion of the T-cell receptor alpha chain.
• The resulting “Stealth” CAR-Tregs are able to evade the CD3 antibody therapy that typically targets T-cells.

Background & Context

Current organ transplantation standards of care require lifelong immunosuppression, which increases the risk of malignancy and infection. While Chimeric Antigen Receptor Regulatory T cells (CAR-Tregs) targeting donor antigens can suppress alloimmune responses while preserving protective immunity, their effectiveness is often limited by the presence of a substantial pool of alloreactive memory T-cells in transplant recipients.

Significance & Outlook

By combining selective depletion of activated T-cells with TRAC -/-CAR-Tregs, the immune balance is skewed toward regulation. This approach addresses the challenge of alloreactive memory T-cells and may enhance the translational potential of CAR-Treg therapy by lowering the required cell dose for clinical efficacy. J.Z, T.B and S.C are listed as inventors on a patent application (EP22300582) related to this work.

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