BIOMED Seminar

Title:
Design of a RECYCLABLE CAR with Durable Antitumor Function

Speaker:
Haopeng Wang, PhD
Assistant Professor
School of Life Science and Technology
ShanghaiTech University

Details:
Chimeric antigen receptor-T cell (CAR-T) therapy offers a promising approach for cancer immunotherapy. However, increasing clinical evidence suggests poor CAR-T persistence in patients limits the therapeutic efficacy. Here, we design a new type of CAR recyclable capability to promote in vivo persistence and to sustain antitumor activity. Firstly, we observed that the engagement of tumor antigens induced rapid ubiquitination of CARs, causing CAR down-modulation followed by lysosomal degradation.

Blocking CAR ubiquitination by mutating all lysines in the CAR cytoplasmic domain (CARKR) markedly repressed CAR downmodulation by inhibiting lysosomal degradation while enhancing recycling of internalized CARs back to the cell surface. Upon encountering tumor antigens, CARKR-T cells ameliorated the loss of surface CARs, which promoted their long-term killing capacity. Moreover, CARKR-T cells containing 4-1BB signaling motifs displayed elevated endosomal 4-1BB signaling that enhanced oxidative phosphorylation and promoted memory T cell differentiation, leading to superior persistence in vivo. Collectively, our study provides a straightforward strategy to optimize CAR-T antitumor efficacy by redirecting CAR trafficking.

Biosketch:
Haopeng Wang, PhD, is an assistant professor in the School of Life Science and Technology at ShanghaiTech University. Dr. Haopeng is an experienced immunologist who has studied T cell biology for more than 15 years. He received his PhD while working in the lab of Dr. Dario A. Vignali at St. Jude Children’s Research Hospital, and completed his post-doctoral training in the lab of Dr. Arthur Weiss lab at the University of California, San Francisco (UCSF). In 2015, Dr. Wang started his independent research at ShanghaiTech University. Wang lab aims to use a multidisciplinary approach to achieve a better understanding of T cell signaling pathways, which would be beneficial for the development of therapeutic strategies for immune disorders and cancer immunotherapy.