Novel 3-Gene Signature Modulation to Generate Potentiated CAR T-Cells

Overcoming CAR T-cell dysfunction in solid tumors by modulating a novel 3 -gene signature.

Background

CAR T-cell therapies have shown remarkable clinical success in hematologic malignancies. Their utility in solid tumors remains a challenge and they have yielded only modest benefits for patients with solid cancers. A critical barrier to therapeutic efficacy in solid tumors is CAR T-cell dysfunction. Preclinical models have nominated several additional “armoring” modifications some of which confer clinical benefit. However, prioritizing which modifications to move to the clinic based on this knowledge alone remains challenging.

Technology

To prioritize modifications that will confer potent clinical benefits to CAR T-cells, Seattle Children’s researchers have undertaken a novel approach. They identified a single T cell clone that mediated a remarkable clinical response in a patient solid tumor, expanding from undetectable levels to an estimated 14.7 billion CAR T-cells and led to a 47.4% reduction in tumor burden in the first 16 days of treatment. Systematically dissecting this response, they identified that modulating CCDC6, CBLB and ASB2 leads to enhanced expansion and tumor killing in CAR T-cells. In a hepatocellular carcinoma mouse model, they were able to achieve significant in vivo cellular expansion and superior tumor elimination by modified GPC3 CAR-T cells.

This technology can be paired with cytokine armoring and inducible gene expression providing a modular system that can be utilized for T cell based adoptive cell therapies. This 3-gene modulation technology effectively overcomes T cell dysfunction, offering a potent and durable therapeutic profile that was derived from human biology rather than preclinical modeling.

Benefits

  • Enhances T cell durability

  • Modular technology; combinable with cytokine armoring

  • Broad applications across CAR T, TCRT, TIL, and iPSC derived T cell therapies

  • Allows integration of safety switches to manage toxicities like cytokine release syndrome

Applications

  • Solid tumor cellular immunotherapy

  • T cell based cellular immunotherapy

  • Adoptive and in vivo cell therapy