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Yixin Wang, Pharmsci graduate student (Hu Lab), will be defending her PhD research thesis:

Engineering Cells and Extracellular Vesicles for Tumor Immunotherapy

Abstract:
Tumor immunotherapy activates the immune system to recognize and eliminate cancer cells, offering a potent, targeted, and durable treatment option. In particular, cells and extracellular vesicles can be engineered to enhance immunotherapy by leveraging both their natural properties and programmable functions. This dissertation presents several strategies for engineering chimeric antigen receptor (CAR)-T cells, platelets, and pyroptotic vesicles as therapeutic effector cells, drug-delivery carriers, and tumor vaccines.

First, to enhance the infiltration and efficacy of CAR-T cells against postsurgical tumor recurrence, we harnessed the wound-homing tropism of platelets by conjugating them to B7-H3.CAR-T cells, thereby directing CAR-T cells to the postsurgical tumor sites. RNA-sequencing results further revealed that platelet activation contributed to the downregulation of genes associated with T-cell exhaustion. Next, to broaden the application of platelet-based delivery, we designed a fusion protein that could target tumor neovasculature and locally trigger coagulation. This created a "cellular hive" that recruited platelets engineered with immunotherapeutics such as the anti–PD-1 antibody (aPD-1). The resulting localized delivery of aPD-1 robustly activated T cells and suppressed tumor growth.

We then applied an engineering approach to extracellular vesicles and developed a tumor vaccine based on pyroptotic vesicles collected from pyroptotic cells. These vesicles were loaded with an immunostimulant and embedded in a biocompatible hydrogel for implantation into the postsurgical cavity. In multiple mouse models, this vaccine stimulated antigen-specific T cell responses, inhibited recurrence and metastasis, and prolonged mouse survival.

In summary, these findings demonstrate that engineered cells and extracellular vesicles represent a promising strategy for enhancing tumor immunotherapy, increasing efficacy while maintaining a favorable safety profile.