Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Diffuse large B cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma in the U.S., is often curable with initial treatment. However, outcomes of the ~40% of patients who experience disease recurrence are dismal. Although stem cell transplantation and CAR T cell therapy salvage a subset of patients, most are not candidates for these aggressive treatments or will relapse after receiving them. Thus, relapsed DLBCL remains a critical area of unmet need. Recently, an immunotherapy that stimulates cancer cell engulfment by macrophages through blocking a “don’t eat me” protein called CD47 has shown promising activity in relapsed DLBCL patients when administered with the anti-CD20 antibody, rituximab. However, only 30-40% of patients achieve lymphoma regression after receiving this treatment. My laboratory has devised innovative approaches to enhance CD47 blockade therapy efficacy in relapsed DLBCL. First, by inhibiting a key signaling pathway in macrophages, we can enhance their “appetite” for DLBCL cells in the context of CD47 blockade in vitro. Second, we have developed tools necessary to execute an unbiased genetic screen to identify new and targetable “don’t eat me” proteins on DLBCL cells that enable their escape from macrophage phagocytosis. The major goals of this application are to: 1) enhance the in vivo efficacy of CD47 blockade therapy in DLBCL by disrupting a key macrophage signaling pathway, and 2) identify new “don’t eat me” proteins on lymphoma cells that can be targeted alone and in combination with CD47 blockade therapy. While DLBCL is our focus, many cancers employ mechanisms to evade engulfment. Thus, our results are expected to have broad cancer relevance.
