2018 Early Career Investigator Grant Recipient — Chunsheng Li, PhD

Chunsheng Li, PhD

University of Pennsylvania

Imaging Guided Immunotherapy Targeting CD248 for Epithelial Ovarian Cancer

Project Summary

Antibodies recognizing specific tumor targets can be used to deliver therapeutic payloads with high degree of specificity. The simultaneous use of antibody against same target for imaging and for therapy, an approach named “theranostics”, offers unique opportunities for precision medicine and rapidly assessing therapeutic response at molecular level. The first example of such antibody-based theranotics is Herceptin in HER2-positive breast cancer: Herceptin is used as companion diagnostic imaging tool as well as the targeted therapy.

To develop effective anti-tumor vascular therapeutics, one needs a robust biomarker, AND a good antibody that can specifically bind to the target. We and others have found one for EOC: CD248/TEM1. It is present at high level in tumor and its microenvironment in EOC and almost absent in normal organs. Importantly, CD248 is expressed by >90% EOC patients on the tumor or tumor vasculature, and its high expression correlates with poor survival. This means that if we can target it, we may destroy tumor but leave normal tissues intact. We also have developed robust antibody against CD248 (78Fc panel, US Patent 61/639,325). We showed that our patented antibodies can find the biomarker and upon binding deliver a payload, for imaging or therapeutic, to CD248-expressing cells. Surprisingly, we found such immunotherapies only directly kill, but also induce significant lymphocyte infiltration into tumors. In addition, tumor rejection was observed upon re-challenging in preclinical models (in submission). Such immune activation we observed could in turn sensitizing previously “cold tumor” EOC, to checkpoint inhibitors such as PD-1/CDLA4.

This project intends to develop companion diagnostics and antibody-immunotherapy with this antibody: screening methods (such as antibody-based immunoPET and serum ELISA) to identify patients with EOC that can be treated with anti-CD248 drugs; we will then develop drugs that are linked to the antibody (such as antibody-drug conjugate) so it can be delivered to the tumor directly to kill. In addition, combined with PD-1 blockade, how ADC therapies exert antitumor immune response to sensitize “cold” tumors that previously resistant to PD-1 therapy.

Bio

Chunsheng Li, PhD, is a Research Assistant Professor in the Department of Obstetrics and Gynecology at the University of Pennsylvania. Dr. Li graduated B. Sc. in Environmental Biology and Ecology from Peking University. He subsequently received an M.Sc in Protein Engineering and Plant Genetic Engineering from Peking University. Dr Li completed his Ph.D. in Microbiology and Immunology under the supervision of Professor Jacek J. Hawiger at Vanderbilt University. Having focused on molecular mechanism and protein engineering of adaptor proteins in innate immunity during his doctoral research, he pursued post-doctoral training in the laboratory of Professor George Coukos in the Ovarian Cancer Research Center at the University of Pennsylvania, where he worked to develop antibody-targeted cancer imaging and therapeutics. His research has been published in leading journals. In addition to the OCRA’s prestigious Liz Tilberis Award, he has been fortunate to win several awards including the Sandy Rollman Foundation, Tina’s Wish Foundation, the Ovarian Cancer SPORE pilot through the Fox Chase Cancer Center, and pilot grant from the American Cancer Society.

His current research interests include cancer targeted theranostics and the creation of innovative platforms for drug delivery by combining the tools of antibody engineering, immunology, molecular biology, and nanotechnology. He is extremely grateful for the generous support of the OCRA, which is enabling his group to investigate the impact of antibody-targeted therapy on cancer and immune cells in the ovarian tumor microenvironment to enable mechanistic determination of antibody targeted therapy. It is hoped that invoking the immune system by antibody-drugs could generate a memory response that might improve the magnitude and frequency of responses, leading to improvement of treatment outcomes of women with ovarian cancer.