Hunter Jonus, PhD

Over the last reporting period, they advanced testing of their PTK7-targeted γδ T cells both in the lab and in animal models, prioritizing strategies that help the cells stay active longer by providing added nutrient support. Early animal studies showed that these engineered γδ T cells can slow tumor growth without notable toxicity. While preliminary testing combining the therapy with immune checkpoint inhibitors did not show clear benefit, the team has identified more promising enhancements to pursue. These include IL-15 secretion and combination with N-803, an IL-15-based drug already being evaluated in neuroblastoma patients. These refinements are now being prioritized as they prepare for IND-enabling studies in the coming months, work that will ultimately supporting moving this therapy toward a future clinical trial.

Over the past six months, they successfully tested PTK7-directed CAR γδ T cells from multiple healthy donors, all of which demonstrated strong tumor-killing activity in neuroblastoma models. The addition of IL-15 further enhanced the function of the CAR T cells, helping them survive longer and stay active. After identifying limitations in CAR γδ T cell manufacturing, the team introduced a new approach-engineered γδ T cells that secrete STARs (Secreted T cell ActuatoRs)-to activate both modified and unmodified cells and improve overall effectiveness. These STAR γδ T cells showed promising tumor-killing activity and offer a potential solution to overcome previous manufacturing challenges. The team is now actively testing this enhanced therapy in combination with other therapies, such as immune checkpoint inhibitors, with plans to begin IND-enabling studies of the lead candidate by the end of Year 3.

They have successfully generated these CAR T cells and tested their efficacy and ability to traffic to the tumor site in vitro. Despite unexpected challenges in CAR expression, they have overcome these hurdles and are continuing to test their effectiveness with or without secretion of IL-15, a cytokine known to enhance T cell survival and activity. Additionally, they have established the infrastructure to produce the necessary components for these studies in-house, reducing the reliance on commercial suppliers and paving the way for faster, more cost-effective research. Furthermore, the team has explored how to effectively combine γδ T cell therapy with immune checkpoint blockade (ICB). To this end, they have identified TIGIT and TIM-3, inhibitory receptors that can limit T cell function, as key factors influencing γδ T cell activity. The team is now performing in vitro testing to enhance the effectiveness of this approach by combining γδ T cell treatment with anti-TIGIT ICB to block these inhibitory signals.