Nanobiologic training of innate immunity to treat disease

Immunotherapy is revolutionizing the sophistication with which cancer is treated and the success with which it is cured. However, the numerous immunotherapies that are currently being developed typically engage the adaptive immune system. In recent years, emerging evidence has shown that the innate immune system displays long-term changes in its functional program, through epigenetic programming of primarily macrophages and monocytes. This innate immune memory has been termed ‘trained immunity’. I hypothesize that targeting trained immunity provides a powerful framework to regulate the delicate balance between immunity and immune tolerance. This proposal’s overall aim is to develop an innovative, yet clinically viable, treatment paradigm in which innate immune cells are specifically targeted – and ‘trained’ – by drug-loaded nanobiologics. A trained immunity-engaging nanobiologic library, containing high density lipoprotein derived nanomaterials with different immunomodulatory payloads, will be established by advanced microfluidics technology. In melanoma, nanobiologic immunotherapies will be selected to prime the immune system to ‘reject’ malignancies, while nanobiologics that promote organ acceptance will be applied in transplantation. These treatment scenarios are superficially unrelated, but – immunologically viewed – represent two sides of the same coin. In this application, I propose to pursue the following Key Objectives (KOs): KO1 establish nanobiologic library technology to regulate trained immunity; KO2 develop trained immunity-promoting nanobiologics to treat melanoma and amplify existing immunotherapies’ efficacy; and KO3 apply trained immunity-inhibiting nanobiologics to prevent heart allograft rejection. The work will be conducted in melanoma and heart allograft mouse models, and will be fostered from the vantage points of bioengineering, imaging, immunology and disease. This program’s successful completion will yield targeted immunotherapies not only to treat melanoma and transplant rejection, but, more generally, conditions in which an immune response needs to be provoked or inhibited, including a range of malignancies, sepsis, autoimmune disorders and cardiovascular disease.