Plasma exchange and radiation resensitize immunotherapy-refractory melanoma: a phase I trial

Immune checkpoint inhibitors (ICI) are effective for advanced melanoma. However, most develop ICI resistance. Tumor-derived soluble PD-L1 (sPD-L1) and other immunosuppressive factors drive resistance. We hypothesized that therapeutic plasma exchange (TPE) may remove sPD-L1 from circulation and overcome ICI resistance. Patients with metastatic ICI-resistant melanoma and elevated sPD-L1 received radiotherapy to a minority of metastatic lesions, TPE, and ICI re-challenge. Primary endpoints were adverse events and sPD-L1 reduction. Secondary endpoints included overall survival, response, and progression-free survival. Correlative studies included changes in sPD-L1, other immunosuppressive factors, and immune cell phenotypes. Eighteen patients were included. Treatment was well-tolerated, and levels of sPD-L1 were reduced by TPE (mean 78%, p < 0.0001). Soluble PD-L1 suppression predicted overall survival. The overall response rate was 61% (16.7% complete, 44.4% partial, 22.2% stable, and 16.7% progressing). Changes in peripheral immune cell populations and immunosuppressive factors predicted overall survival. sPD-L1 and other circulating immunoregulatory molecules mediate ICI resistance. TPE can reduce these factors and resensitize ICI-refractory melanoma. Patients with persistent elevation or rapid rebound of sPD-L1 experienced inferior outcomes, suggesting that multiple courses of TPE may be necessary. These findings may apply to other ICI-resistant cancers. Trial registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1).