Research Abstract
I have a longstanding interest in interaction between the immune system and cancer. As a dissertation student with Dr. Glenn Dranoff’s lab at Dana-Farber Cancer Institute, I established the first model of lung cancer caused by a defect in immune regulation. In this model, deficiencies in the cytokines GM-CSF, IL-3 and IFN-γ, lead to a combination of tumor promoting inflammation and defective antitumor immunity that produces highly penetrant pulmonary adenocarcinomas. This work provided early pre-clinical data supporting a dual role for the immune response in lung cancer, with failure of adaptive immunity combining with innate inflammation to drive lung cancer development. These findings were subsequently validated in clinical trials of checkpoint blockade which confirmed a role for adaptive immunity in controlling lung cancer, and in the CANTOS trial which demonstrated reduced lung cancer incidents in patients treated with antibodies that block the innate inflammatory cytokine IL-1β.
My dissertation work also identified a novel regulatory role for the Inhibitor of Apoptosis (IAP) family of proteins in T cell activation through NF-B signaling downstream of TNF family costimulatory receptors. I used pharmacologic IAP inhibitors to study the therapeutic implications of this finding, combining IAP antagonists with a tumor vaccine to augment antitumor responses. This finding was the basis for subsequent work that has exploited the immune modulating properties of IAP antagonists to treat multiple myeloma and glioblastoma in preclinical models, and is now being investigated in multiple clinical trials.
As a resident and Gastroenterology fellow at Massachusetts General Hospital (MGH), I joined Dr. Hidde Ploegh’s lab at the Whitehead Institute for Biomedical Research, where I generated and characterized single domain antibodies (VHHs) to several immune receptors. I used these VHHs for multiple pre-clinical applications. By fusing VHHs to cytokines, I developed a panel of modified cytokines with novel binding properties and improved therapeutic effects in a variety of mouse models. I showed that VHHs against CD47 can enhance responses to murine melanoma in combination with immune modulating antibodies, and in my own lab, have established a syngeneic model for evaluating the toxicities of CD47 targeted therapeutics. By tagging these VHH to radioisotopes, I worked with two other postdoctoral fellows to comprehensively image PD-L1 in a live mouse, and to track CD8 T cells responses in mice undergoing immunotherapy using immuno-positron emission tomography (PET). PD-L1 PET unexpectedly showed that PD-L1 is primarily expression by brown adipose tissue (BAT), and is an activation-independent marker for brown adipocytes, a finding with implications that I continue to explore in my own lab.
As an independent investigator, I have focused my efforts on understanding the etiology and immune mechanisms underlying the immune-related adverse events (irAEs) resulting from cancer immunotherapy, a window into the endogenous function of the immune receptors targeted by these therapies. My research dovetails with my clinical work, where I specialize in treating gastrointestinal (GI) irAEs resulting from “checkpoint” receptor blockade, which are often treatment limiting. Management relies on systemic corticosteroids, which are likely to have deleterious effects on antitumor responses. My goal is to use a detailed mechanistic understanding of gastrointestinal irAEs to develop novel treatment strategies that do not interfere with antitumor immunity, as well as to understand on a more fundamental level, how individual immune receptors regulate immune homeostasis in the GI tract.
