Project Term: July 1, 2022 - June 30, 2025
The goal of this project is to explore a novel immunologic therapeutic target for hematologic malignancies, SIGLEC15 (Sig15). The central hypothesis is that Sig15 is aberrantly expressed in malignant B cells, is released to attenuate immune responses and can be targeted therapeutically to promote immune responses to malignant hematopoietic cells. This work will accelerate therapeutic exploitation of the immune system for the treatment of leukemia and lymphoma by targeting Sig15.
Treatment for B cell malignancies, such as B cell acute lymphoblastic leukemia (B ALL) and non-Hodgkin’s lymphoma (NHL) are still not successful enough, so new strategies are urgently needed. Strategies that use the immune system to eliminate cancer cells are promising, but the understanding of how malignant B cells avoid the immune system is incomplete, which slows the development of these new strategies. Our long-term goal is to develop new treatment strategies for leukemia and lymphoma based on better understanding of how malignant B cells escape immune responses. The objective of this project is to generate knowledge about a new way to treat leukemia and lymphoma by targeting Siglec15 (Sig15). The hypothesis is that leukemia and lymphoma cells express Sig15, which inhibits the immune system, and that Sig15 can be inhibited to promote a strong immune response. This hypothesis is supported by strong preliminary data from our lab. Little is known about Sig15 in leukemia and lymphoma, so the proposed studies are necessary to justify clinical trials targeting Sig15. With this project, we will 1) determine mechanisms of abnormal expression and release of Sig15 from malignant B cells, 2) Define how Sig15 changes the immune response to malignant B cells, and 3) Determine whether targeting Sig15 improves existing immune therapies for leukemia and lymphoma. Aim 1 will be achieved with various molecular biology techniques to measure Sig15 levels in leukemia and lymphoma cells, focusing on the NF-kB signaling pathway, which appears to regulate its expression. Aim 2 will be achieved by measuring T cell function when cultured together with leukemia cells with and without Sig15 inhibition, and by quantifying immune cell recruitment and activation in mice with B cell malignancies with or without Sig15. Aim 3 will be accomplished by testing the efficacy of blinatumomab and CAR T cells with a monoclonal antibody against Sig15. The project is innovative because of its focus on Sig15 as a new immune modulating target for hematologic malignancies, which have generally not been susceptible to other immune checkpoint inhibition strategies. This work will be significant because it will accelerate development of clinical trials targeting Sig15 for the treatment of leukemia and lymphoma.