Targeted IL-12 Nanodelivery by CAR T Cells in Combination with PD-L1 Blockade for Enhanced Cancer Therapy

The development of chimeric antigen receptor (CAR)-T cell therapies has seen significant advancements in treating blood cancers, yet challenges remain in enhancing their efficacy and minimizing side effects. A new approach involves the use of a CRISPR activation system to control the expression of IL-12, a cytokine that can potentially transform a hostile tumor microenvironment into one that supports immune response.

A novel CAR-T cell therapy, RB-312, targets the HER2 receptor and is equipped with a CRISPRa system designed to trigger the production of IL-12. This system consists of two components: one that expresses a HER2-specific CAR with co-stimulatory domains and another that encodes a fusion protein capable of activating the IL-12 gene upon interaction with the CAR component.

In vitro tests have shown that this CAR-T cell therapy can boost the production of interferon-gamma, enhance cytotoxicity, and improve CAR-T cell proliferation. In vivo studies have demonstrated prolonged persistence of the therapy and increased suppression of cancer cell growth, with no detectable systemic IL-12, thus reducing the risk of systemic toxicity. The combination of this therapy with PD-L1 blockade has also shown promising synergistic effects.

RB-312 represents an innovative CAR-T cell therapy that leverages a CRISPRa system for non-editing, reversible upregulation of IL-12, which could lead to better persistence and effectiveness against HER2-expressing tumors while limiting the risk of off-target effects and systemic toxicity.