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

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

Abstract 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...

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Main Authors: Jacob J. Orme, Henan Zhang, Prashanth Lingamaneni, Yohan Kim, Roxane Lavoie, Maddy Dorr, Paul Dizona, Jacob Hirdler, Elizabeth A. Bering, Joanina K. Gicobi, Michelle Hsu, Heather Dale, Daniel S. Childs, Lisa A. Kottschade, Robert R. McWilliams, Matthew S. Block, Aaron S. Mansfield, Svetomir N. Markovic, Ken Olivier, Dawn Owen, Scott Lester, Daniel Ma, Roxana S. Dronca, Haidong Dong, Fabrice Lucien, Annie T. Packard, Jeffrey L. Winters, Sean S. Park
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-57865-9
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Summary:Abstract 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).
ISSN:2041-1723

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