Novel Concept, ‘Immune Dimming,’ Explored in Rheumatoid Arthritis

LONDON — In yet another effort to repurpose oncology drugs for autoimmune disease, a researcher reported here that low doses of blinatumomab (Blincyto) given to patients with treatment-resistant rheumatoid arthritis (RA), while not reprogramming the immune system to a fully normal state, did restore patients’ responsiveness to more conventional RA drugs.

Of 15 patients receiving blinatumomab under this protocol, initially all of them obtained some degree of clinical improvement, with 11 achieving ACR50 response (50% reduction in RA severity by American College of Rheumatology criteria), but 14 of the group relapsed after a mean of 5 months, according to Laura Bucci, MD, of Friedrich-Alexander-Universität Erlangen-Nürnberg in Germany.

Some of those 14 were then treated again with targeted disease-modifying anti-rheumatic drugs (DMARDs), usually the same ones they had previously tried and failed — and this time, a majority showed responses that lasted up to 6 months, she told attendees at the European Alliance of Associations for Rheumatology’s (EULAR) annual meeting.

The concept, Bucci said, is called “immune dimming,” in that it does not “reset” the immune system to terminate all anti-self activity, as is the goal with chimeric antigen receptor (CAR) T-cell therapy, pioneered a few years ago for autoimmune diseases by Georg Schett, MD, at the same institution. (Schett is a co-author for the current study.)

How low-dose blinatumomab works to restore DMARD responsiveness in these patients, all of whom had previously received multiple targeted therapies without lasting success, remains uncertain, Bucci acknowledged when an audience member asked following her talk. “We need more patients and more studies” to figure that out, she said.

Both for oncology and rheumatology, blinatumomab is an unusual drug. It’s considered a “bispecific T-cell engager”: it has two different protein-binding elements, one that binds the CD19 antigen on B cells, the other targeting the CD3 T-cell protein on T cells, inducing the latter to destroy the former. The drug is approved for a variety of B-cell malignancies, but — as with CAR T-cell therapy, also originally developed for such cancers — it might also be adapted for autoimmune conditions driven by rogue B cells.

RA hasn’t traditionally been considered one of those, but B cells are still involved in it; autoantibodies are present in most RA cases (albeit with uncertain pathological importance). An earlier presentation at EULAR this week (also, naturally, with Schett as co-author) found that CAR T-cell treatment could indeed lead to remission in heavily pretreated RA.

The new study is actually a follow-up to one Bucci had reported 2 years ago at EULAR, in which six patients at that point had received low-dose blinatumomab. Findings then were very positive, with all six patients showing strong clinical and biomarker responses. Treatment then was provided to nine additional patients, with similarly positive early responses.

Blinatumomab was administered in two or three cycles, starting with 9 μg by infusion, raised to 28 μg in the second cycle for some patients. Those given a third cycle got the same dose as in the second.

However, closer examination revealed that B cells were not fully depleted within lymph nodes, and as noted above, all but one of the patients relapsed over the following months. Some reduction in immunoglobulins were seen but they were not as deep as with CAR-T treatment. Autoantibodies rebounded in many patients after the initial decline.

Bucci said some patients were retreated with blinatumomab, but they still had the same pattern of initial response followed by relapse. Consequently, it was decided to try again with standard targeted DMARDs in a subset of the cohort. Qualitative results were as follows:

• Five patients had previously received abatacept (Orencia); two were retreated; one showed a significant response
• Five patients had previously received a JAK inhibitor; four were retreated; all four showed significant responses
• Three patients had previously received a tumor necrosis factor inhibitor; all three were retreated; two showed significant responses

In total, eight patients remained on DMARD therapy with follow-up of 11 to 18 months after completing the blinatumomab regimen.

One patient of the 14 who relapsed after blinatumomab was lost to follow-up and another was not restarted on a regular DMARD but was instead given teclistamab (Tecvayli), also a bispecific T-cell engager, which also failed.

Bucci said controlled studies are required to determine whether “immune dimming” is a viable approach in RA, or, for that matter, other autoimmune disorders.