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Answers leading to more questions:
Understanding ECP’s potential mode of action in GvHD

Despite extracorporeal photopheresis (ECP) being used to treat chronic graft versus host disease (cGVHD) since the 1990s,1 scientists are still investigating its mode of action.2

But understanding the mechanisms that drive its efficacy in diverse and complex clinical conditions is key to the continued improvement of patient care, said Dr Nick Matthews, senior research scientist at Rotherham NHS Foundation Trust.

We spoke to Dr Matthews, 2018’s Advancing ECP Immunomodulation Investigator Award winner, about how his team’s research is impacting perceptions of ECP and helping drive the charge towards personalised medicine.

A place for macrophages

At Rotherham’s Photopheresis Research Unit, Dr Matthews and his colleagues Ms Charlotte Burton and Dr Arun Alfred have been busy investigating the mechanisms that make ECP work in GvHD, a potentially serious complication of allogeneic stem cell transplantation.

It’s a mystery experts have been working to unravel for decades – and, as the researchers have confirmed over the last few years, it is one that can generate more questions than answers.

“Back in 2017, a study reported a factor called soluble CD163 (sCD163) to be increased in patients with de novo and active chronic GvHD,”3 said Dr Matthews.

He explained that the factor, which is released by activated monocytes and macrophages, had previously been considered a biomarker of fibrotic disease, such as systemic sclerosis.4

But this study suggested it could also be used as a biomarker of the effect of therapeutic modalities, such as ECP, cGvHD, he said.

His team set up a pilot study of 18 cGvHD patients and found those with high levels of sCD163 at baseline saw those levels fall substantially over three months of ECP treatment.5

“Because sCD163 is released by activated macrophages, this pointed to ECP might have an effect on the activation of macrophages in vivo,” explained Dr Matthews.  “It opened up a whole new world.”

Traditionally, most GvHD understanding has been concentrated on lymphocytes – such as T-cell and B-cell involvement – yet this finding added to a growing body of evidence pointing to the role of macrophages, he said.

“There have been studies showing how macrophages in various in vivo models could have a significant role and that macrophage depletion could reduce chronic GvHD”.

Determined to delve further into this “under-investigated area”, Dr Matthews’ team applied for, and won, Mallinckrodt’s inaugural Advancing ECP Immunomodulation Investigator Award, in 2018.

The educational grant of €50,000 supported their initial research by helping to expand their work and increase the power of the study.

“It meant a lot to the team. We were very honoured and glad for the recognition and the support to answer fundamental questions about monocytes and macrophages in the context of treating cGvHD patients with ECP,” said Dr Matthews, pointing to the abstract presented at EBMT 2020 for more information.5

A question raised with the research funding – and highlighted at this year’s EBMT – was the survival and cytokine production capacity of monocytes from cGvHD patients following ECP.6

This work gave them yet another question to answer, and the team next worked to generate macrophages from GvHD patient monocytes, then examine the effect of cells, such as neutrophils, treated with ECP.

“But that’s as much as I can tell you without sharing the unpublished data,” joked Dr Matthews.

“It is the nature of research that trying to understand and answer what you think is a simple question then begets a whole family of new questions,” he added.

Personalised care

Understanding the mechanisms of ECP is a vital area of research, particularly as we move into the personalised care era.

“ECP has been around for a long time, and it’s incredible how diverse cGvHD patients are: the diversity of the symptoms, the duration of symptoms, the severity of symptoms.,” said Dr Matthews.

“Every patient is a universe in themselves.”

Better understanding of ECP and its mode of action is one way to help clinicians better tailor treatment to a person’s particular symptoms and disease course, said Dr Matthews. But there are still more questions to answer.

“What we are doing is investigating the potential for better, more refined, more personalised ECP in the future.

“That’s the ultimate aim,” he concluded.

References:

  1. Owsianowski, M., Gollnick, et al.  (1994). Successful treatment of chronic graft-versus-host disease with extracorporeal photopheresis. Bone marrow transplantation, 14(5), 845-848.

  2. Mankarious, M., Matthews, N. et al. Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD). Frontiers in Immunology, 11 (2020): 81.

  3. Inamoto, Y., Martin, P. J., Paczesny, S., et al. (2017). Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease. Biology of Blood and Marrow Transplantation23(8), 1250-1256.

  4. Nakayama, W., Jinnin, M., et al.  (2012). Serum levels of soluble CD163 in patients with systemic sclerosis. Rheumatology international, 32(2), 403-407.

  5. P192: Effect of Extracorporeal Photopheresis on Production of Serum Soluble CD163: Relationship to Immunosuppression and Disease Activity in Chronic Graft Versus Host Disease, EBMT 2020.

  6. P051: Effect of Extracorporeal Photopheresis on Enrichment, Survival and Cytokine Production Capacity of Monocytes from Chronic Graft versus Host Disease Patients, EBMT 2021