Plasma Exchange Isn’t Going Anywhere: Immunotherapy Is Writing Its Next Indications
Recently, in a group chat of early-career transfusion medicine physicians, I heard a familiar claim: therapeutic plasma exchange (TPE) is headed toward irrelevance, edged out by newer immunotherapies. I understand why people say it. I also think it’s wrong, and the reason is a trial in melanoma.
The Argument for Obsolescence
Hear me out on the other side first. Medicine does retire procedures. When a targeted drug does the job more precisely, the blunt instrument loses its place, and TPE is about as blunt as instruments get. It removes plasma, along with whatever is dissolved in it, good or bad. If a drug can hit a single pathogenic target, why take everything out?
Where TPE Shines
My answer is that some situations still need a blunt instrument. TPE has a durable role in acute management, where something harmful has to come out now, and in refractory disease, where the targeted option has already failed. I don’t expect immunotherapies to replace either role.
What I expect instead is that immunotherapies will create new indications. I’ve already written about one: TPE for immune checkpoint inhibitor (ICI) encephalitis, where TPE manages a toxicity of immunotherapy itself. That is a problem that didn’t exist before checkpoint inhibitors, and TPE has a new category of indication in treating it.
There is a second, newer category, and it involves not the toxicity of immunotherapy but its failure.
The Decoy Problem
ICIs work by blocking the interaction between PD-1 on T cells and PD-L1 on tumor cells. Resistance, where a tumor that responded stops responding or never responds at all, is common. One proposed contributor is soluble PD-L1 (sPD-L1), a form of the ligand shed into the circulation. It binds PD-1 directly and can dampen antitumor immunity despite ICI treatment [1]. Other soluble checkpoint molecules, including sPD-L2, sTIM3, sB7H3, and sLAG3, may play similar roles [1]. Think of them as decoys: a drug aimed at a receptor has to compete with whatever is flooding the blood.
A procedure that removes plasma can clear the decoys. Orme and colleagues previously showed that TPE removes sPD-L1 from circulation [2].
The Trial
In 2025, the same group published a phase I trial, ReCIPE-M1, in Nature Communications [1]. Eighteen patients with metastatic, ICI-refractory melanoma and elevated sPD-L1 received stereotactic body radiotherapy (SBRT) to a minority of their lesions, then three daily TPE sessions with albumin replacement, then re-challenge with anti-PD-1 therapy.
TPE reduced sPD-L1 by a mean of 78%. The overall response rate was 61%, with 16.7% complete responses. Median overall survival was 17.4 months [1]. For context, the authors point to an earlier randomized trial in PD-1-refractory melanoma, where ipilimumab alone produced a 9% response rate and ipilimumab plus nivolumab produced 28% [1].
The Honest Part
The study was single-arm and open-label, and it combined three treatments, so there is no way to tell how much of the benefit came from TPE versus SBRT. It enrolled 18 patients, all White and non-Hispanic. The correlative analyses had no adjustment for multiple comparisons.
And the biology also keeps pushing back. sPD-L1 came back fast, recovering to a median of 60% of pre-TPE levels by the second ICI cycle, and patients with a rapid rebound did worse. The authors suggest serial TPE may be needed [1].
There are practical issues too, and they are ones that transfusion medicine has to think about. Two screened patients were excluded for poor venous access, and one patient developed a grade 4 sepsis and a grade 3 thromboembolic event tied to a vascular access device [1].
Where This Leaves Us
I don’t think TPE is headed toward irrelevance. I think the map of TPE indications is going to keep redrawing itself as immunotherapies advance, with new indications appearing in the gaps these drugs create. If ReCIPE-M1 holds up, the open questions will be ours to answer. How many sessions does it take to keep the decoys down? And which patients need it?
References
Orme JJ, Zhang H, Lingamaneni P, et al. Plasma exchange and radiation resensitize immunotherapy-refractory melanoma: a phase I trial. Nat Commun. 2025;16:2507. https://doi.org/10.1038/s41467-025-57865-9
Orme JJ, et al. Therapeutic plasma exchange clears circulating soluble PD-L1 and PD-L1-positive extracellular vesicles. J Immunother Cancer. 2020;8. (As cited in reference 22 of the trial paper.)
