Every year, approximately 1.5 million new patients are diagnosed with solid tumors in the United States. Most of them will undergo surgery, based on the premise that a major resection leads to longer survival. Nonetheless, surgery is often considered a palliative venture with no hope of cure, as many tumors infiltrate vital organs or critical structures that cannot be excised. The long-term goal of our research proposal is to develop an implantable biomaterial device to eradicate residual tumor that cannot be resected by surgery. Currently, no adjuvant therapy is available that completely removes tumor deposits left behind after surgery. One of the most promising treatments being tested in tumor patients is transfusion of tumor-reactive lymphocytes, referred to as adoptive cell therapy (ACT). However, the clinical application of ACT is severely limited by poor tumor trafficking of infused lymphocytes and limited cell persistence within the tumor. As a result, treated patients almost always ultimately relapse with disease. The specific hypothesis guiding this application is that the ability of tumor-reactive T-cells to eradicate incompletely resected tumor can be dramatically enhanced by providing a sustained release of appropriately stimulated T-cells into the tumor resection cavity from a bioactive material vehicle. Our group has designed and tested porous polymer scaffolds that, sponge-like, soak up select tumor-reactive T-cells along with molecules that help the cells multiply and activate. Cell-loaded scaffolds can be directly implanted during surgery into the tumor resection cavity, where they disperse T-cells in a depot manner into surrounding tissue. At the same time, scaffold-released immune stimulants could activate the host immune system to destroy untreated distal tumors. Our hypothesis will be addressed with the following aims: (1) to enhance the efficiency of biomaterial vehicles in expanding embedded tumor-reactive T-cells and dispersing them into surrounding tissue, (2) to examine the ability of material-mediated T-cell delivery to prevent tumor relapse more effectively than conventional T-cell injections, and (3) to test whether co-delivering immune stimulants from implanted scaffolds can substantially enhance ACT and trigger systemic host antitumor immunity. Our interdisciplinary studies could provide the first demonstration that a biomaterial delivery system can enable tumor-reactive lymphocytes to eradicate tumor, while conventional cell transfusions have no curative effect. We believe that biomaterials and technologies arising from our studies can easily be plugged in to a wide range of established surgical protocols and provide surgeons with a potentially curative treatment option for tumors that currently can only be managed by palliative surgery, such as in pancreatic cancer, brain tumors, sarcomas or breast cancer.
Cancer relapse after surgery is often the ultimate cause of death. The device developed in our studies could protect patients from disease recurrence and substantially improve their survival and quality of life, while cutting down on healthcare costs due to expensive follow-up surgery or palliative care.
|Smith, Tyrel T; Moffett, Howell F; Stephan, Sirkka B et al. (2017) Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest 127:2176-2191|
|Stephan, Sirkka B; Taber, Alexandria M; Jileaeva, Ilona et al. (2015) Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat Biotechnol 33:97-101|