PROBLEM

Exhausted CD8 T cells significantly limit the effectiveness of immunotherapies and cell therapies in cancer and chronic viral infections. Persistent antigen exposure drives durable epigenetic reprogramming that locks T cells into a dysfunctional state, silencing effector and memory-associated genes while promoting inhibitory pathways. Although immune checkpoint blockade (ICB) therapies can transiently reinvigorate partially exhausted T cells, they fail to rescue terminally exhausted populations, resulting in low response rates and relapses. There remains a critical unmet need for strategies that directly reverse the epigenetic and metabolic programs sustaining T cell exhaustion and restore long-term function.

SOLUTION

Dr. Hazem Ghoneim has identified a short-chain fatty acid (SCFA)-derived small molecule that serves as a novel dual metabolic and epigenetic regulator capable of reversing T cell exhaustion. Using advanced in vitro models of terminal exhaustion in both human and mouse CD8 T cells, this unique SCFA restores effector function, enhances cytokine production, improves cytotoxic activity, and promotes memory-like characteristics. Mechanistically, the SCFA remodels transcriptional circuitry by upregulating effector and memory-associated genes while suppressing critical exhaustion drivers, such as the NR4A family. In a mouse solid tumor model, treatment with the SCFA compound reduces tumor burden, increases progenitor-like T cell populations, and enhances responses to ICB. Similarly, in vivo models of viral infection demonstrate the SCFA-derived compound strengthens anti-viral CD8 T cell responses, decreasing viral load. Thus, this approach leverages a durable epigenetic modification to reprogram immune cells to exhibit sustained anti-tumor and anti-viral activity.

APPLICATIONS

Combination therapy with ICB and adoptive T cell therapies for treatment of cancer or chronic viral infections

ADVANTAGES

• Dual-action approach to improve functionality: metabolic and epigenetic modulation of CD8 T cells to prevent exhaustion and promote memory-like characteristics
• Promotes durability: preserves progenitor-like T cell populations to boost long-term immunity
• Broadly applicable to a variety of cancers, including solid tumors and hematological malignancies, and viral infections
• Synergistic with existing ICB and cell therapies

Seeking opportunities for out-licensing, co-development, and collaboration