An Engineered Nanoimmunotherapy for Melanoma

PROJECT SUMMARY Melanoma is one of the most prevalent cancers and is estimated to account for overdeaths inin the United States aloneAlthough highly curable when detected earlytheyear survival rates decline precipitously for patients with regionaland metastaticmelanoma indicating a lack of efficacy of conventional therapiesand a strong need for novel therapies for this patient populationIn response to this needwe have engineered a nanoimmunotherapy for treating melanomawhich combines Prussian blue nanoparticle based photothermal therapyPBNP PTTwith immune checkpoint inhibitionImmune checkpoint inhibitors represent a class of monoclonal antibodies that target key immune checkpointswhich have resulted in dramatic treatment responses in previously untreatable cancersparticularly metastatic melanomaDespite this immense promiseresponses to immune checkpoint inhibitors are limited to small subsets of patients and are associated with immune related adverse eventssome of which can be lethalThusthere is great need to increase the efficacy of immune checkpoint inhibitors so that they elicit responses in a greater proportion of treated patientsOur approach toward achieving this end is to engineer a nanoimmunotherapy which combines PBNP PTT with anti PDand anti CTLAIn our nanoimmunotherapyPBNP PTT plus anti PDplus antiCTLAPBNP PTT serves the dual purpose of ablating the primary tumor to decrease tumor burden and releasing tumor antigens to provide amulti antigen vaccination effectThese effects are complemented by the administration of immune checkpoint inhibitorswhich decrease tumor immunosuppression and elicit a potent antitumor immune responseWe anticipate that the interplay between the local immunomodulatory effects of PBNP PTT with the reversing of immunosuppression elicited by the antibodies will result in complete response and long term survival in a larger proportion of patients with melanomaThe goal of this project is to test the feasibility of using this nanoimmunotherapy for treating melanoma in a syngeneic mouse model of the diseaseIn Aimwe seek to demonstrate the efficacy of the nanoimmunotherapy in securing effective tumor eradication and preventing relapseIn Aimwe seek to elucidate the immunological responses elicited by the nanoimmunotherapySuccessful completion of this project will facilitate further preclinical development of our nanoimmunotherapy in animal models of metastatic melanomaand ultimately clinical testing and commercialization of our treatment regimen PROJECT NARRATIVE The proposed research is relevant to public health because it could make available an effective and safe treatment for melanomaa prevalent type of cancer that is expected to account for overdeaths inin the United StatesIt will also advance insights into the scientific merit and feasibility of combining nanoparticle based photothermal therapy with immune checkpoint inhibition for treating melanoma in animal modelsand the immunological basis for the observed treatment responsesSuccessful completion of this project will facilitate future studies testing this combination nanoimmunotherapy in animal models of metastatic melanomaan important prelude to clinical translation and commercialization of this treatment for patients with melanoma