A method of enhancing cancer immunotherapies through androgen receptor modulation

­Summary
The current technology has the potential to enhance the effectiveness of checkpoint blockade for advanced prostate cancer patients by directly enhancing T cell function through a reduction in intrinsic androgen receptor signaling.

Technology Overview
In many patients with advanced cancer, immunotherapy treatments have largely failed. Mechanisms of immunotherapy resistance are varied and represent tumor cell intrinsic mechanisms of treatment escape as well as tumor microenvironment mechanisms of resistance. Hormones such as androgens, represent one possible mechanism of immunotherapy resistance.

Recent work by the laboratory of Amy Moran identified that androgen receptor signaling not only promotes tumor cell growth but also acts directly on T cells to limit their function (see Publication). Based on this finding, the current technology is an immune cell genetically engineered to have reduced androgen receptor expression and methods for enhancing the effectiveness of immunotherapy checkpoint inhibitors by administering the genetically engineered cells in combination with immune checkpoint blockade therapy.  Proof of concept data has demonstrated:

• Androgen receptor signaling within T cells limits anti-tumor function and T cell responsiveness to immunotherapy by inhibiting the interferon gamma pathway.
• Reduction in T cell androgen receptor activity, via either genetic depletion or pharmacological blockade, improved checkpoint inhibitor efficacy and mouse survival rates.
• A utility for a wide array of cell therapies, including CAR-T cell therapy, allogenic T cell therapy, dendritic cell-based vaccines, macrophage therapy, myeloid/macrophage antigen receptor therapy, natural killer cell therapy, etc.

Publication
Guan, X., et al. “Androgen receptor activity in T cells limits checkpoint blockade efficacy.” Nature 606, 791–796 (2022). Link

Licensing Opportunity
This technology is available for licensing.