BME PhD Prospectus Presentation: Yuyan Cai

Title: "Engineering synNotch receptors for solid-tumor diagnosis and immunotherapy"

Advisory Committee: Dr. Wilson Wong, PhD - BME (advisor) Dr. Hadi Nia, PhD - BME (chair) Dr. Liangliang Hao, PhD - BME Dr. Pawel Przytycki, PhD - CDS

Abstract: Chimeric antigen receptor (CAR) T-cell therapy is effective against blood cancers but has largely failed against solid tumors, which cause most cancer deaths. Both detecting and treating solid tumors are limited by the same problem that few antigens are truly tumor-specific. A single antigen cannot distinguish tumor from normal tissue, causing false positives in detection and on-target/off-tumor toxicity (OTOT) in therapy. Engineered cells can supply this missing specificity by integrating more than one signal through logic gating. Synthetic Notch (synNotch) receptors are well suited to this, as they decouple antigen sensing from output. Aim 1 develops an AND-gated synNotch sensor that reports co-expression of two antigens as secreted nanoluciferase measurable in blood and urine. Aim 2 develops a polymer-primed IF-THEN synNotch–CAR circuit in which poly(Fibrin-FITC) localizes to tumor fibrin and primes an anti-FITC synNotch that induces an anti-ROR1 CAR, restricting CAR activity by location. Together, these aims establish a modular synNotch platform that improves detection specificity and reduces off-tumor toxicity.