Developing multipronged cell therapy for RMS
| A new strategy for pediatric sarcoma: Reprogramming the tumor’s defenses Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. For children whose cancer has spread or returned, the prognosis is dire, with survival rates under 30%. Traditional treatments have plateaued, and a new strategy is urgently needed. Current advanced immunotherapies, such as Adoptive Cell Therapy (ACT) – often called “living drugs” – frequently fail because the tumor fights back in two key ways: 1. It sends “death signals” that kill the therapeutic T cells. 2. It recruits immune cells called macrophages into the tumor microenvironment (TME) that act as “bodyguards” to protect the cancer cells. Our approach: Our project proposes a pioneering “multipronged” T-cell engineering strategy to overcome both of these critical barriers simultaneously. We start with FGFR4 CAR-T cells, which are T cells genetically modified to recognize and target a key cancer driver (FGFR4) found on RMS cells. We are equipping these CAR-T cells with two novel genetic tools: 1. A Fas Switch Receptor (Fas SR): This tool is designed to make the T cells highly resilient and persistent by neutralizing the tumor’s “death signals” and instead giving T cells a “boost”. This is essentially to “replace a brake with an accelerator” for T cells. 2. A CD40L Fusion Protein (FP): This tool is designed to reprogram the tumor bodyguards. It converts the immunosuppressive macrophages from cancer protectors into active cancer destroyers that attack the tumor cells, essentially turning the TME from hostile to helpful. Preliminary data: We show in our studies that using the Fas SR in combination with FGFR4 T cells leads to increased eradication of RMS cells. Additionally, we discovered that CD40L FP T cells successfully reprogram the macrophages, causing a significant increase in their ability to eliminate tumors. Project goal: Our project has two main goals (Aims) focused on optimizing these two new tools in living models of cancer. By using a living model (mice) with human tumors and T cells, we will more accurately evaluate how our strategies help T cells infiltrate tumors and reprogram immune cells, providing more informative results than just combining T cells and tumor cells in the lab. We aim for a first-in-class clinical trial that offers a new hope for pediatric RMS patients by delivering a highly durable T cell therapy that actively dismantles the tumor’s defense systems. |