SITC 2020 Richard V. Smalley, MD, Memorial Lectureship Speaker
Yale Cancer Center
Richard V. Smalley, MD, Memorial Lectureship
Wednesday, Nov. 11 at 10 a.m. EST
Why were we interested in immunity within the tumor microenvironment in the 1990s?
Dr. Chen studies immune cell communications via cell surface protein-protein interactions. He is also interested in translating laboratory findings to treat human diseases including cancer, autoimmune diseases and infection.
In 1992, Dr. Chen showed the first proof-of-concept study that the B7-CD28 family molecules could be the targets for cancer immunotherapy. This study inspires subsequent studies targeting the B7-CD28 family molecules for the treatment of human cancer.
In 1999, Dr. Chen, then at the Mayo Clinic, first to discover a molecule he called B7-H1, which is now also known as PD-L1. He subsequently showed that PD-L1 is expressed by several types of tumors and that its activity can cause the death of T cells, thus preventing them from eliminating cancer cells. Bringing these lines of inquiry full circle, he later showed that blocking this interaction between PD-1 and PD-L1 by monoclonal antibodies improved the immune system’s ability to eliminate tumors in a 2002 paper. Chen’s work provided an important foundation for the subsequent development of immunotherapies designed to block this activity, and thereby enable more effective immune responses against cancer. Dr. Chen also initiated and help organized the first-in-man clinical trial of anti-PD-1 monoclonal antibody for treating human cancer in 2006, when he moved to the Johns Hopkins Medical Institute, and developed PD-L1 staining as a biomarker to predict treatment outcome. His discoveries directly led to the development of anti-PD-1/PD-L1 antibody therapy against broad spectrum of human cancers. These discoveries have revolutionized cancer treatment.
Other important breakthroughs made by Dr. Chen's laboratory include the development of an agonist antibody against the 4-1BB co-stimulatory pathway, also known as CD137. Multiple 4-1BB-targeting antibodies have since been developed and are now being evaluated in clinical trials for a variety of cancer types. Dr. Chen’s laboratory also discovered various molecular pathways with T cell costimulatory and coinhibitory functions and/or their applications in human disease treatment. These pathways include B7-H2 (ICOSL), B7-H3, B7-H4, B7-H5/CD28H, PD-1H (VISTA), TNFRSF19, RELT, LIGHT/HVEM, B7-H2/CD28/CTLA-4 (human), SALM5/HVEM, FGL1/LAG-3, Siglec-15 etc. Many of these findings are now being developed clinically for the treatment of human diseases.