Dr. Stone is an award-winning immunologist with expertise in T cell immunology, immuno-oncology, and human immunology. As VP of Oncology at GigaGen she is advancing antibody therapies with best-in-class potential. Previously Dr. Stone was Assistant Professor at The Wistar Institute Cancer Center where her independent laboratory focused on understanding the multiple mechanisms of action of first-generation immune checkpoint inhibitors, including anti-CTLA-4, with the goal of identifying strategies to overcome resistance. She was awarded several grants for her research including the Melanoma Research Alliance’s Bristol-Myers Squibb-MRA Young Investigator Award and funding from the NIH. She also held the position Wistar Institute Assistant Professor of Pathology and Laboratory Medicine at the Perlman School of Medicine at the University of Pennsylvania where she was a member of the Institute for Immunology, the Immunology Graduate Group Executive Committee, and the Gene Therapy and Vaccines Program. Dr. Stone is an active member of the American Association of Immunologists (AAI), where she serves as Chair of the AAI-Clinical Immunology Committee. Dr. Stone was the 2017 recipient of AAI’s Chambers-Thermo Fisher Scientific Memorial Award. She has published numerous manuscripts in journals including Immunity, Nature Reviews Immunology, Science, Cancer Immunology Research, ELife, and PNAS, mentored students and postdoctoral fellows, and served as a reviewer for study sections and journals. Dr. Stone holds a B.S. in Biology summa cum laude from the University of New Hampshire and a Ph.D. in Biological Sciences from UC-San Diego where she also completed a postdoctoral fellowship.
Anti-CTLA-4 antibodies such as ipilimumab were among the first immune-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. Here we present evidence that checkpoint inhibition may not be the primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, a primary mechanism for efficacy is FcR-mediated Treg depletion in the tumor microenvironment. We identified a monoclonal antibody (mAb), GIGA-564, that binds to CTLA-4 at an epitope that differs from ipilimumab’s by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, GIGA-564 has superior anti-tumor activity compared to ipilimumab in a murine model. GIGA-564 also induces less Treg proliferation and has increased ability to induce in vitro FcR signaling and in vivo depletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of GIGA-564 likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that GIGA-564 was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition.