Xuexiang Du

Title : Safe and effective immunotherapy by targeting CTLA-4

Abstract:

Cancer immunotherapy is becoming a powerful and acceptable treatment to malignant tumor in addition to traditional methods such as surgery, radiotherapy and chemotherapy. Anti-CTLA-4 monoclonal antibodies confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAEs). How to uncouple the undesired irAEs from the beneficial CITE seen in cancer patients treated with anti-CTLA-4 and/or other immunotherapies has proven to be a daunting challenge, partially due to the lack of the understanding of the real MOA(mechanism of Action) of CITE and irAEs. First, we discovered that the immunotherapy of current anti-CTLA-4 mAbs were dependent on Fc/Fc receptor mediated intra-tumor Treg depletion rather than the widely held mechanism of checkpoint blockade, which raised the reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy; Second, we establish one realistic irAEs model and reveal one new mechanism of irAEs, while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.

Biography:

Dr. Du obtained his PhD in Chinese Academy of Sciences in 2015. After he finished postdoctoral fellowships and Research Associate in the University of Maryland, Baltimore, he returned to China and be a full Professor in Shandong University. He focuses on cancer immunotherapy to dissociate the undesired immunotherapy related adverse events from the beneficial immunotherapies. April 25, 2022, the U.S. FDA has granted Fast Track designation to ONC-392, the next-gen anti-CTLA-4 monoclonal antibody (mAb) which he developed , as a single agent for the treatment of patients with metastatic  NSCLC  who have had disease progression on prior anti-PD-(L)1 therapy.