12 December 2019

The long road to RA immunotherapy

Clinical Rheumatology

The most sophisticated treatments for rheumatoid arthritis that we have right now, biologic DMARDs and targeted synthetic DMARDs, target the tail-end of the inflammatory process.

But what if we could stop the disease process upstream, before it even started causing pain and discomfort in patients?

This is the dream that has kept Professor Ranjeny Thomas working on an immunotherapy for RA for the past two decades.

Professor Thomas is a rheumatologist at the University of Queensland Diamantina Institute whose team performed the world’s first trials of the dendritic cell immunotherapy in patients with RA in 2015.

The therapy is still under development but, if it works, it might be able to rewind the very early autoimmune responses in people who don’t yet have full-blown RA, and prevent people from progressing beyond the first transient symptoms, making it kind of like an RA vaccine.

At this year’s annual conference for the American College of Rheumatology (ACR) in Atlanta, Professor Thomas presented the results of a human trial for a nanoparticle therapy, DEN-181, which employs a similar strategy as the dendritic cell therapy.

Professor Thomas is not alone in exploiting the activity of dendritic cells to treat autoimmune diseases. Other research teams around the world have been trialling this approach for RA, type 1 diabetes, coeliac disease and multiple sclerosis.

HOW IT WORKS

RA immunotherapy works by exploiting the action of dendritic cells.

Dendritic cells are white blood cells that reside in the lymph nodes. They are often called the “generals” of the immune system because they tell other cells what to do.

Dendritic cells have several different roles.

First, dendritic cells can tell the T cells to respond to infections by presenting foreign antigens on their surface.

Second, they can secrete pro-inflammatory cytokines such as TNF-? and IL-6, which form targets for RA drugs like TNF inhibitors and IL-6 receptor inhibitors.

Third, dendritic cells with regulatory properties can promote regulatory T cells, which suppress the action of autoreactive T cells (these are the troublemakers in diseases such as RA).

There are different approaches to making immunotherapies for RA. On way is to extract dendritic cells from people with RA and modify them so they talk to the immune system differently.

 The researchers do this by exposing the dendritic cells to rheumatoid self-peptides in-vitro so they start to present these autoantigens on the outside of their cell.

At the same time, the researchers inhibit a particular cell pathway, called the NF-?B pathway, to regulate dendritic cell behaviour.

 By inhibiting the NF-?B pathway, this turns the dendritic cell into an autoimmune regulator instead of an autoimmune promoter. So, instead of encouraging the action of autoreactive T cells, the dendritic cell is now programmed to regulate autoreactive T cells.

 The dendritic cell therapy is then injected back into the patient’s skin so it can migrate to the lymph nodes and control self-reactive T cells.

Taking blood samples from patients with RA to extract dendritic cells and then specifically modifying those cells in the lab is a time-consuming and expensive process.

What researchers are now doing is bundling RA self-peptide and vitamin D3 (to inhibit the NF-?B pathway) into nanoparticles called liposomes and then delivering the particles to the skin. 

The nanoparticles then migrate to the lymph nodes and target dendritic cells there, achieving the same effect on self-reactive T cells.

LOOKING BACK

It was back in 2001 that Professor Thomas’s team first started to crack the secrets of dendritic cell function which would form the mechanistic basis for an RA immunotherapy.

“We were working on dendritic cells, and we were trying to understand what makes them function so well as antigen-presenting cells,” she says.

“And in order to do that we were looking at pathways that were activated when they were activated. And then we had to block that pathway in order to show that it was important. And then when we blocked it, we found that they induced tolerance.”

Researchers have come and gone over the years. Dr Brendan O’Sullivan and Dr Nigel Davies at the University of Queensland Diamantina Institute also deserve credit for the discovery of the liposome-based immunotherapy that has been applied in RA.

But Professor Thomas is the only person from the original team still working on the project.

“It’s pretty much a roller-coaster,” she says. “It’s really just a matter of keeping the final vision of preventing and curing RA in your mind – which is exciting – and then working through the problems that come up, solving them and getting to the next thing that you need to do along the way.”

The progress from laboratory to product is a step-by-step process, she says.

The University of Queensland spin-off company Dendright was formed in 2005 to commercialise the discovery, with Professor Thomas as a director. Janssen invested in Dendright for the indication of RA in 2012.

Professor Thomas’ team has been working on two different kinds of therapies.

The first was a dendritic cell injection called Rheumavax. Dendright then developed the liposome nanoparticle therapy called DEN-181 in partnership with Janssen.

“The dendritic cell injection is basically taking the cell that you want to target from the body, modifying it with a drug in a test tube and then putting it back into the patient.

“And then the liposome packages RA self-peptides and drug together so that after injection into the skin it actually targets the dendritic cells in the body.”

DEN-181 is of greater commercial interest than dendritic cell therapy because it can be manufactured as a product and administered to people with RA or people at high risk of RA, says Professor Thomas.

“Whereas, with the dendritic cell injections every person has got their own cells going back in,” she says. “So, it’s much harder to do consistently.”

In 2015, the researchers trialled Rheumavax (the dendritic cell injections) in 18 patients with seropositive RA.

This study showed that a single injection of Rheumavax appeared to have a positive effect, reducing the effector T cells and increasing the ratio of regulatory to effector T cells after one month.

It was a proof of concept study that demonstrated what might be possible with immunotherapy in RA. It opened the door to commercial development of a nanoparticle therapy, says Professor Thomas.

The liposome nanoparticle, DEN-181, is still in the early stages of development, says Professor Thomas.

A recent trial of DEN-181 in 17 patients, presented at ACR in November, found the therapy was safe and modulated antigen-specific T cells in RA patients of appropriate HLA genotype.

The 0.3ml dose suggested “a skew toward immunological tolerance”, which is good news for the researchers who want to take the next step in developing nanoparticle immunotherapy for RA.

“This was a first-in-human exploratory trial of a very novel immunotherapy – one that aims to disrupt the way we treat RA in the future,” says Professor Thomas.

“We have learned and continue to learn a tremendous amount as we analyse the results and the blood samples from this trial.”

OVERSEAS RESEARCH

There are currently three dendritic cell therapy trials for rheumatoid arthritis listed on the US clinical trials website: one in France, one in Russia and the other in the UK.

Dr John Isaacs, a professor of clinical rheumatology at Newcastle University in the UK, and one of the researchers listed has been working in this area since 2005, is preparing for phase II clinical trials next tear.

His team is looking at a dendritic cell therapy rather than an off-the-shelf nanoparticle approach, he says.

The research is exciting because it has the “potential to ‘switch off’ the disease, providing long-term benefit from a short intervention”, he says.

“It is individual-specific in that it is manufactured from the patients’ own blood cells,” he says.

“It is a cellular therapy, which is unusual in itself. Dendritic cells control the immune system (we call them the generals) and so if we can create a tolerogenic dendritic cell it should correct the mistakes that the immune system has made.

“So, rather than non-specifically suppressing the immune system, it only corrects the parts that have gone wrong – a very specific and selective treatment, which should have very minimal side effects.

“It could certainly be used as a preventative treatment once it is shown to be effective in established disease.”

References:

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients, Science Translational Medicine, 3 June 2015 – paper

2771 A Phase I, Randomized, Double-blind, Placebo-controlled, Single Center, Single-dose Escalation to Investigate the Safety, Tolerability, and Pharmacodynamics of Subcutaneously Administered DEN-181 in Adult Patients with ACPA+ Rheumatoid Arthritis on Stable Methotrexate, ACR, 12 November 2019 – conference abstract

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