Grant: Project Grant

Soft tissue sarcomas are rare but aggressive cancers that arise from connective tissues such as muscle, fat, and bone. Despite surgery, radiation, and chemotherapy, many patients experience cancer recurrence or spread to other parts of the body, which is often fatal. One major reason sarcomas are so difficult to treat is that they actively suppress the immune system, making modern immune-based treatments less effective. CAR T cell therapy is a form of immunotherapy in which a patient's own immune cells are modified to recognize and attack cancer cells. While CAR T therapy has been very successful in some blood cancers, it has shown limited benefit in solid tumors like sarcoma. This is because CAR T cells often struggle to enter sarcoma tumors, survive within them, and remain active long enough to eliminate cancer cells. This research project will test a new strategy to improve CAR T cell therapy for sarcoma by first "preparing" the tumor using a treatment that activates a natural immune pathway called STING. Activating STING inside a tumor can stimulate immune activity and make the tumor environment more supportive of an immune attack. We will study whether giving this immune-activating treatment before CAR T therapy helps CAR T cells better enter sarcoma tumors, stay active, and control cancer growth. We will also examine whether radiation therapy can produce similar immune-preparing effects in tumors that cannot be directly injected. In addition, this project explores a new idea for improving how CAR T cells are made. By activating the immune system before collecting immune cells for CAR T manufacturing, it may be possible to create CAR T products that can recognize cancer cells in more than one way, which could improve treatment effectiveness. Together, this work aims to develop new immune-based strategies to make CAR T cell therapy more effective for patients with sarcoma and support future clinical trials.