�鶹AV

Dr. Yukai He obtained his MD from Southern Medical University, China, and PhD in Molecular Virology from University of Heidelberg, Germany. He finished his postdoc training in University of Pittsburgh. His laboratory is focused on studying the basic mechanism of genetic immunization with viral vectors and on developing immunotherapy for solid tumors. Since 2010, Dr. He’s research has been developing T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells to treat primary hepatocellular carcinoma (HCC) and head and neck cancers. One of the TCR genes identified from his laboratory is licensed to a biotech company by �鶹AV and is undergoing clinical trials. 

• TCR engineering of human T cells for immunotherapy of hepatocellular carcinoma 

Liver cancer is the 5th most common cancer and the 3rd most common cause of cancer death in the world. According to the Centers for Disease Control and Prevention, the incidence rate of liver cancer has doubled over the last 20 years, making it the fastest growing cancer in the US, especially for minority groups such as Hispanic and Black Americans. Engineering patient’s autologous T cells with AFP (HCC tumor associated antigen)- specific T cell receptor (TCR) genes offers a specific immunotherapy approach for HCC. In this project, we plan to 1) identify hAFP-specific TCRs to create TCR-Ts of different functional avidity, 2) identify the hAFP-specific TCRs without or with minimal cross-reactivity, and 3) create expandable and removable TCR-Ts with stemness to achieve stronger in vivo antitumor effect. The goals are to obtain the optimal TCR genes that can engineer primary human T cells to become effective TCR-T cells capable of killing human HCC cells without harming normal cells and to establish protocols for generating safe and effective TCR-T cells that are ready for clinical trials. This will eventually lead to new therapeutic approaches for HCC. In 2020, the TCR developed from this study entered into clinical trials (NCT03971747). 

• Developing novel moderate affinity “Fast-On/Fast-Off” chimeric antigen receptor T cells (CAR-Ts) effective for solid tumors 

The second project in my lab is to develop novel CAR-Ts with moderate-affinity Fast-On/Fast-Off engaging kinetics for HCC and head and neck cancers (HNC). The efficacy of solid tumor CAR-Ts remains low despite intensive effort. Current CAR designs have been focusing on decreasing tonic signaling, enhancing CAR-T infiltration, improving the tumor microenvironment (TME), and reducing toxicity and immune escape. Nevertheless, such efforts result in only incremental improvement. Most CARs are built with high-affinity antigen-binding domains (ABD), the majority of which are monoclonal antibodies, mAbs. However, T cell activation may not need high-affinity engagement. For example, the affinity of T cell reporter (TCR) for MHC/peptide complex is 3 logs lower than mAb binding antigen. We have been working on T cell engineering with both TCR and CAR, which prompt us to interrogate the importance of ABD affinity in CAR-T’s function. We recently showed that low affinity CAR-Ts expanded more, underwent less activation-induced cell death/exhaustion (AICDE), persisted longer, and generated durable antitumor effects. We reason that the current CAR affinity is too high and the engaging time with tumor cells is too long, which are unnecessary, cause off-tumor toxicity, and drive CAR-Ts to AICDE, especially in solid tumors. We hypothesize that ABD with optimal affinity and engaging kinetics will enable CAR-Ts to effectively kill tumor cells without being driven into AICDE and allow CAR-Ts to avoid off-tumor toxicity. The goal is to develop safe and effective CAR-Ts for solid tumors of head/neck cancer (HNC) and hepatocellular carcinoma (HCC) by studying the affinity and engaging kinetics of CAR-Ts with tumor cells. Currently this project is funded by a intramural Paceline Cancer Research Award. We are actively seeking NIH grants to fund this highly impactful research.