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Cancer immunotherapy has demonstrated great potential for treating cancer. However, challenges such as 1) the lack of ideal targetable tumor antigens; 2) severe toxicity due to off-target interactions; and 3) tumor-mediated immunosuppression are limiting the success of immunotherapies to be broadly applicable. To potentially overcome these challenges, Dr. Wu and his colleagues have developed a programmable synthetic gene circuit platform that enables tumor-localized therapeutic payload production, for recruitment and activation of immune cells: Tumor Immuno-therapy by Gene-circuit Engineered Response (TIGER). This strategy makes use of the body's own immune system to kill tumor cells. Gene circuits (highly engineered DNA sequences that work together), delivered systemically, will be turned on by the presence of two cancer-specific signatures, therefore only be activated within cancer cells and not normal cells. Cancer cells will be forced by the activated gene circuits to produce immunomodulators. Dr. Wu has demonstrated that TIGER mediates robust therapeutic efficacy in vivo in solid tumors. They have also identified sensors that can distinguish high-grade stem-like glioma cells from non-stem-like glioma cells. To further accomplish clinical translation of this platform, several advances are required: 1) identification of tumor sensors that efficiently detect highly heterogeneous primary patient tumors, to optimize tumor-targeting efficiency and specificity; and 2) optimization of therapeutic output combinations for achieving maximal efficacy. This project will focus on advancing the above two aspects to facilitate clinical translation of TIGER to treat pediatric high-grade glioma and overcome existing barriers to effective immunotherapy.

The first year of this grant is funded by and named for the Kai Slockers Pediatric Cancer Research Fund. Kai was diagnosed at 2½ with Atypical Teratoid Rhabdoid Tumor (ATRT), a rare and very aggressive brain cancer. Within two weeks of diagnosis, he passed away, a mere 3 months shy of his third birthday. When Kai took his last breath, the cloudy sky opened up with a bright ray of sun that streamed through the windows of his hospital room – the darkness of the disease was replaced with the light of hope and the peace of no more suffering. Whenever the sun is out, his family thinks of him, assured that his legacy of hope shines on. In his brief life, Kai shared his warmth, energy, goofy sense of humor, and caring heart with all those he met. This Hero Fund was created in his memory and will support research to help other kids with cancer have a better chance to fight and survive. It has a special focus on brain tumor research, specifically treatments that could minimize the harsh effects of brain tumor treatment. The Slockers family hopes to continue his legacy of light and hope through the funding of childhood cancer research.

A portion of this grant is generously supported by the Derick the Defeater Fund, a St. Baldrick's Hero Fund. Derick was a hero in so many ways. Diagnosed with medulloblastoma at the age of six, he endured 2 years of treatment with determination and a positive spirit. He inspired friends and family with his smile and charisma, even advocating for other children fighting cancer and teaching everyone what it meant to be brave. Derick’s courage lives on in a comic book his friends created called “Derick the Defeater” about a superhero who fought evil villains that looked like cancer cells. This Hero Fund honors his legacy of helping others through the funding of childhood cancer research.