Seminar Abstract:

The major problems in the current therapy for oncologic diseases include its inability to selectively target specific tumor cells in the surrounding tissues that make it hard for the drugs and treatment to reach the tumor cells. Despite the significant progress in the discovery of surface markers, targeting ligands, and biomaterial carriers, very few nanoparticle drugs are truly tumor-specific after intravenous injection and their targeting is still not fully reliable, which results in a wide distribution of nanoparticles throughout the body and increases the chance of adverse side effects. To overcome such limitations, my graduate research implemented immune cells as living targeting and delivery vehicles that deliver therapeutic biodegradable photoluminescent polymer (BPLP)-based nanoparticles to two tumor models, melanoma and glioblastoma. This system takes advantage of the inherent targeting and penetrating capabilities of immune cells into the tumor target and the fluorescent properties of BPLP nanoparticles for in vivo imaging. Our platform technology allows assembling various types of nanoparticles, drugs, imaging agents, and immune cells as a treatment for different diseases in the future. The second part of the seminar introduces how the immune cells can also be genetically engineered for cancer immunotherapy in vivo. Even with huge success in the development of CD19-targeting chimeric antigen receptor (CAR) T cells for B-cell hematological malignancies, we still face major challenges in expanding adoptive cell transfer for solid tumors. To expand this adoptive cell therapy, finding the right targets for solid tumors that are tumor- and tumor microenvironment-specific is the foremost important step. During my postdoctoral work, we have found an epitope within the collagen alpha-3(VI) (COL6A3) gene, which can be used as a biomarker to target stromal cells associated with multiple solid tumors. COL6A3-specific TCRs were isolated and one of these TCRs was affinity enhanced so that the T cells expressing TCR variants that preserved COL6A3 specificity and endowed both CD4 and CD8 T cells with augmented effector functions were able to specifically eliminate tumors in vivo that expressed similar amount of peptide-human leukocyte antigen (pHLA) as primary tumor specimens with favorable safety profile with no detectable off-target reactivity. These preclinical findings serve as the basis and rationale to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors. As a principal investigator, my lab will first focus on merging immunology, synthetic biology, genetic engineering, material science, and biomedical engineering to develop and evaluate the next generation T cell-based therapies that target and kill solid tumors with enhanced specificity, reduced toxicity, and the ability to overcome tumor-associated immunosuppression.