Overcoming immune checkpoint inhibition with therapeutic plasma exchange and radiotherapy in melanoma

Project Narrative Gold standard clinical trials in metastatic melanoma have demonstrated significantly improved survival with immunotherapy (e.g. immune checkpoint inhibitors; anti-PD1 and anti-PD-L1). However, only about 35% of all patients benefit and almost all patients eventually develop resistance to immunotherapy and succumb to their cancer. Stereotactic body radiotherapy is a highly advantageous treatment modality in melanoma due to its ability to overcome radioresistance and allow patients to mount an immune response against melanoma that can synergize with immunotherapy, also known as the abscopal effect. Despite these advanced therapies, melanomas develop resistance by releasing immunosuppressive molecules (sPD-L1 and evPD-L1) in the blood that kill activated immune cells directed against melanoma. Therefore, we propose to incorporate therapeutic plasma exchange (a safe and commonly used therapy in patients with autoimmune disease) to remove immunosuppressive molecules and overcome melanoma therapy resistance and rescue anti- melanoma immunity brought by radiotherapy and immunotherapy.