A recent study conducted at the Mayo Clinic highlights the potential of therapeutic plasma exchange (TPE) to overcome resistance to immune checkpoint inhibitors (ICI) in patients with advanced melanoma. This groundbreaking research, spanning from December 2020 to February 2023, explored how TPE can effectively reduce levels of soluble PD-L1 (sPD-L1), which has been linked to the diminished effectiveness of cancer treatments involving ICIs.
Melanoma, particularly when advanced, has proven to be resistant to various treatment modalities, including PD-1 inhibitors. Soluble PD-L1, produced through proteolytic cleavage, binds to PD-1 receptors on immune cells, thereby suppressing the body's anti-tumor immunity. High plasma levels of sPD-L1 have been associated with poorer responses to ICI therapy, leading researchers to investigate whether TPE could counteract this issue.
During the study, researchers screened 34 patients with metastatic melanoma progression on anti-PD-1 therapy. Out of these, 18 patients met eligibility criteria, with an average age of 63. Each participant received stereotactic body radiotherapy (SBRT) targeting selected metastatic lesions, followed by three daily treatments of TPE, and then re-challenging with ICI therapy. This comprehensive approach aimed to reinvigorate patient responses to ICI therapies by first reducing the suppressive factors present within their systems.
The results were promising. TPE was found to significantly decrease sPD-L1 levels by 78% on average (p = 310^-5). Notably, the median recovery rate of sPD-L1 before the second ICI re-challenge was 60% of the pre-TPE levels (p = 5.810^-4), indicating effective control over sPD-L1 rebound, which is often associated with inferior patient outcomes.
Outcomes following the combination approach were notable: the overall response rate (ORR) reached 61%, with 16.7% of patients achieving complete responses, and 44.4% experiencing partial responses. This was particularly significant for patients who had undergone extensive pre-treatment regimens. According to the authors of the article, “therapeutic plasma exchange can reduce these factors and resensitize ICI-refractory melanoma.”
Survival data from the study also reflected the efficacy of this new treatment paradigm. The median overall survival (OS) for participants was recorded at 17.4 months with the median follow-up extending to 21.2 months. Analysis revealed those whose sPD-L1 levels remained below pre-TPE levels at the time of the second ICI re-challenge experienced superior overall survival (hazard ratio HR = 0.1, 95% CI 0.02-0.51, log rank p = 0.0009).
One of the unexpected findings was the impact of sPD-L1 levels on overall survival rates. Patients who exhibited elevated or quickly rebounding sPD-L1 levels during treatment faced inferior outcomes, pointing to the necessity of possibly repeating TPE for those individuals. This observation suggests future research may benefit from exploring more regular TPE treatments to maintain low sPD-L1 levels, thereby potentially improving patient outcomes.
Interesting correlations were also observed within different immune cell populations. Changes noted among tumor-reactive CD8+ T cells and regulatory T cells over the course of treatment indicate possible predictors of survival, underpinning the biological mechanisms at work during the TPE and ICI re-challenge setup. Patients with increasing levels of regulatory T cells experienced lower OS (HR 9.72, 95% CI 2-47.3, p = 0.005), emphasizing the role of immune cell dynamics during cancer treatments.
Importantly, the study was characterized by minimal adverse events, with reported issues falling within expected ranges based on previous immunotherapy experiences. The findings from this research propose TPE as both a feasible and promising adjunct to standard therapies for metastatic melanoma.
Overall, the study suggests TPE, combined with SBRT and ICI re-challenge, may provide new hope for treating melanoma by addressing the plateaus of treatment resistance seen with traditional therapies. This study opens avenues not just for melanoma patients but potentially extends to other cancers exhibiting similar patterns of ICI resistance. Future studies are warranted to validate and optimize this therapeutic strategy across varying cancer types.