Transgenes to enhance CAR T cell tumor trafficking

CXCR3 engineered CAR T cells for enhanced CAR T cell migration and accumulation at tumor sites.

Background

CAR T cell therapy has emerged as a powerful strategy to treat hematological cancers; however, effectiveness against solid tumors remains a challenge. One major challenge is in trafficking CAR T cells to solid tumor sites. Engineered T cells frequently fail to efficiently migrate toward and infiltrate into the solid tumor microenvironment. Unlike blood cancers, solid tumors present formidable physical and chemical barriers that actively exclude immune cells from the tumor mass. Consequently, even when engineered cells possess potent tumor-killing capabilities, their clinical efficacy is severely limited by insufficient accumulation at the disease site. This lack of active recruitment prevents therapeutic cells from reaching the necessary density to achieve meaningful tumor eradication.

Technology

To address the CAR T trafficking bottleneck in solid tumors, Seattle Children’s researchers have leveraged the CXCR3CXCL10 signaling axis. Engagement of the tumor by CAR T cells triggers CAR T cell activation and secretion of the chemokine CXCL10. Utilizing this biology, Seattle Children’s researchers have engineered CAR T cells to co-express specific isoforms of the chemokine receptor CXCR3. CXCR3-overexpressing CAR T cells can better sense the concentration gradient of CXCL10 and migrate towards the tumor site, while continuously recruiting additional therapeutic cells in a positive feedback loop.

This technology transforms passive CAR T cell circulation into active, targeted recruitment, overcoming a barrier in solid tumor infiltration. While initially optimized for B7-H3-positive cancers, the CXCR3-mediated trafficking enhancement can be adapted to target different tumor-associated antigens, offering a versatile approach to solid tumor immunotherapy.

Benefits

  • Enhanced CAR T cell trafficking to solid tumors

  • Offers a specialized treatment approach for challenging pediatric brain and spinal cord tumors

  • Modular platform that can be adapted to target different tumor associated antigens across various solid tumors

Applications

  • Solid tumor cellular immunotherapy

  • B7-H3 targeted cancer therapy

  • Pediatric brain and spinal cord tumor therapy