can the promise of combining radiation and genetic/immunotherapy be realized?

Dr. Zhou is interested in the synergistic fields of biomolecular/cellular engineering, radiotherapy, and immunotherapy. She has already had great success identifying and targeting cancer specific proteolytic neoepitopes, offering promising new avenues for immunotherapy. With this Young Investigator Award, she will set her sights on ionizing radiation (IR)-inducible immunotherapy to advance the combination therapy TNFerade, which leverages ionizing radiation (IR) to prompt a targeted and controlled release of TNFα. TNFerade works synergistically with IR to boost tumor eradication. TNFerade, while innovative, failed in phase III clinical trials due to its transient therapeutic effect, limited reach within tumors, restricted tissue/cell specificity, and intratumoral delivery constraints.

To address these limitations, Dr. Zhou plans to engineer a novel IR-triggered gene amplifier that utilizes a positive feedback mechanism to ensure sustained therapeutic levels specifically at the tumor site. Her strategy includes a modular amplifier design, which will enable the integration of various therapeutic genes beyond TNFα. Central to this system is the development of multiple synthetic, IR-inducible dual promoters that can be tailored to various types of cancers and tissues. These dual promoters are designed not only to respond to IR but also to amplify the gene expression once activated. IR directly kills tumor cells while triggers local expression and release of therapeutic molecules to kill surviving cells. The precision of IR-induced transgene activation minimizes the risk of off-tumor toxicity. The consistent release of therapeutic agents, once activated, allows for lower dosage, and supports systemic administration through adeno-associated virus (AAV) vectors. By harnessing IR to drive the persistent expression of therapeutic genes locally, Dr. Zhou aim to enhance the antitumor efficacy and safety across a spectrum of cancer types. Dr. Zhou’s goal is to develop treatment options that are not only more effective but also tailored to the complexities of individual tumors, improving patient outcomes significantly.