THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Rheumatoid immunotherapy moving ahead on two tracks

Ranjeny Thomas, MD, MBBS
Ranjeny Thomas, MD, MBBS

Tolerogenic immunotherapy in rheumatoid arthritis is moving forward in clinical trials. Proof-of-concept trials of dendritic cell immunotherapy have raised interest in their potential as targets for autoimmune disease immunotherapy. Meanwhile, cancer immunotherapy is in clinical use, and rheumatologists are seeing the fallout.

“Many patients getting cancer immunotherapy are developing autoimmune complications,” said Ranjeny Thomas, MD, MBBS, Arthritis Queensland Chair of Rheumatology at the University of Queensland Diamantina Institute, Woolloongabba, Australia. “A better approach for immunotherapy would be an antigen-specific approach that leaves the rest of the immune system untouched. That is what we are working on: Creating a more specific and targeted precision approach to rheumatoid arthritis immunotherapy.”

Dr. Thomas will discuss her work in antigen-specific immune therapy for rheumatoid arthritis (RA) using dendritic cells duringCell-Based Tolerogenic Therapies in Rheumatic Diseaseson Monday from 4:30 – 6:00 pm in Room W183c.

John Isaacs, MD, PhD
John Isaacs, MD, PhD

The symposium co-presenter is John Isaacs, MD, PhD, Professor of Rheumatology and Director of the Institute of Cellular Medicine at Newcastle University, Newcastle Upon Tyne, England. His lab is also developing tolerogenic dendritic cells as a therapy to switch off RA.

Both groups are working toward an immunotherapy that invokes drug-free remission of RA and other rheumatic diseases. Both groups have met Phase 1 safety goals and are in the clinic or planning follow-up trials. Both immunotherapy candidates are based on altered dendritic cells, but that is as far as the similarities go.

Dr. Isaacs’s group removed monocytes from RA patients, differentiated dendritic cell populations, and incubated them with tolerogenic factors plus synovial fluid removed from the patient’s own inflamed knee. The dendritic cells thereby expressed synovial proteins, including autoantigens, in tolerogenic manner in order to induce regulatory T cells, dampening the immune response responsible for inflammation. The expanded cells were injected back into the same patient’s inflamed knee to test their stability.

“We loaded the dendritic cells with the very thing that could tolerize the autoimmune response, but, under different circumstances, could equally exacerbate it,” Dr. Isaacs said. “If the cells proved unstable in an inflamed environment and things got worse rather than better, we could have washed the knee out using an arthroscope and injected glucocorticoid. However, we didn’t encounter such problems. Now, we need to investigate different administration routes and validate immune monitoring to demonstrate that we are dampening down the immune response. That’s Phase 2.”

Dr. Thomas extracted dendritic cells from patients, then incubated and expanded them with an immunomodulatory agent and citrullinated RA antigens. The expanded dendritic cells were injected intradermally.

“There were only minor adverse events, and we had a change in the immune response to be more regulatory,” she said. “We had a reduction in activated T cells and a relative increase in regulatory T cells. It is very promising that you can use dendritic cells to influence a patient’s immune system in a way that relates to their rheumatoid antigen.”

Her group has already launched a Phase 1 trial using nanoscale liposomes packaging RA antigen and an immunomodulatory drug to deliver the same effect.

Whether both or neither of these approaches will eventually succeed in RA is unclear. But the concept of cell-based tolerogenic therapy clearly works in both oncology and in infectious disease.

“We already use the same strategy in vaccines,” Dr. Thomas noted. “Dendritic cells are the target of the antigen we are delivering with any vaccine.”

Dr. Isaacs is equally positive.

“The whole concept of therapeutic tolerance, resetting the immune system such that we switch off things like rheumatoid arthritis, has hit prime time,” he said. “Therapeutic tolerance is the next frontier in terms of therapeutics. If you come to this session, you will hear the cutting edge of the story.”