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).
Authors
- Matthew Stephen Block (ORCID: https://orcid.org/0000-0001-5692-4219)
- Heather Dale
- Dawn Owen (ORCID: https://orcid.org/0000-0002-0538-3202)
- Sean S. Park (ORCID: https://orcid.org/0000-0003-3814-853X)
- Jacob J. Orme (ORCID: https://orcid.org/0000-0002-0319-0239)
- Robert R. McWilliams (ORCID: https://orcid.org/0000-0002-8199-5040)
- Prashanth Lingamaneni
- Michelle S. H. Hsu (ORCID: https://orcid.org/0000-0002-2028-1028)
- Daniel S. Childs (ORCID: https://orcid.org/0000-0001-7643-2836)
- Annie T. Packard (ORCID: https://orcid.org/0000-0002-7919-1887)
- Roxana Dronca (ORCID: https://orcid.org/0000-0002-5345-2268)
- Haidong Dong (ORCID: https://orcid.org/0000-0002-5782-2983)
- Paul Dizona
- Jeffrey L. Winters (ORCID: https://orcid.org/0000-0001-8654-3732)
- Joanina K. Gicobi (ORCID: https://orcid.org/0000-0002-2741-0363)
- Henan Zhang (ORCID: https://orcid.org/0000-0002-5680-4687)
- Roxane R. Lavoie (ORCID: https://orcid.org/0000-0001-6253-8090)
- Ken Olivier
- J. Daniel (ORCID: https://orcid.org/0000-0002-2957-4687)
- Maddy Dorr
- Lisa A. Kottschade (ORCID: https://orcid.org/0000-0001-8922-2619)
- Aaron S. Mansfield (ORCID: https://orcid.org/0000-0002-9483-6903)
- Elizabeth A. Bering
- Scott C. Lester (ORCID: https://orcid.org/0000-0001-5264-9811)
- Svetomir N. Markovic (ORCID: https://orcid.org/0000-0002-9238-4325)
- Fabrice Lucien (ORCID: https://orcid.org/0000-0001-6149-345X)
- Yohan Kim (ORCID: https://orcid.org/0000-0002-4009-1694)
- Jacob Hirdler
Institutions
- Mayo Clinic (US)
- WinnMed (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1038/s41467-025-57865-9
- Citations
- 6
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 6.27
Funders
- National Cancer Institute