When it comes to turning T-cell therapies toward autoimmune diseases, CAR-Ts have been leading the way. But another red-hot modality is also beginning to show potential in the clinic.
One of the most intriguing readouts at the European Alliance of Associations for Rheumatology (EULAR) in London came from Cullinan Therapeutics, which showcased the first data from its phase 1b program of a CD19xCD3-directed T-cell engager (TCE), dubbed CLN-978, in patients with autoimmune diseases.
Of the 17 evaluated patients in the study with systemic lupus erythematosus (SLE), 14 (82%) saw their peripheral B-cell counts reduced by over 80%, Cullinan explained in a poster at the conference. When looking specifically at the 14 patients who received target doses of 20 µg or above, half of these saw their B cells drop so low that they couldn’t be quantified.
Meanwhile, of the 14 patients with SLE who had been followed up at four weeks or beyond, 10 (71%) achieved a four-point or greater reduction in a score of disease activity, according to the same poster.
For the 11 patients with rheumatoid arthritis (RA), Cullinan chose to focus on the six patients who were treated at the target doses. Of these, four saw their B cells drop below the level of quantification.
For Ricardo Grieshaber-Bouyer, M.D., Ph.D., professor of clinical systems immunology at FAU Erlangen-Nürnberg University in Germany, the results are the latest step in the journey of finding the best way to use T-cell-based therapies to treat autoimmune diseases.
“[For] roughly five years, the autoimmune space has been standing upside down because we have seen, initially via CAR-T cell therapy, that a deep depletion of B cells can lead to long periods of drug-free remission, even in the sickest patients,” said Grieshaber-Bouyer, who led Cullinan's study.
“In general, [autologous CAR-T] works great, but it doesn't scale,” he explained to Fierce in an interview on the EULAR sidelines. “It’s clear that individual manufacturing is a massive bottleneck and cost driver, so you want something that's off the shelf.”
Faced with this challenge, researchers currently have three potential options for “off-the-shelf” cell therapies to treat these autoimmune diseases: allogeneic CAR-Ts; in vivo CAR-Ts; and TCEs.
“The most validated category is TCEs,” said Grieshaber-Bouyer, pointing to a dozen approvals for the modality in various forms of cancer.
His first foray into this space was testing how a low dose of blinatumomab—a CD19xCD3 TCE marketed by Amgen as Blincyto to treat leukemia—performed in refractory RA. That study demonstrated a rapid decline in RA clinical disease activity.
Those results encouraged Grieshaber-Bouyer that CD19 is a “very attractive target” when it comes to depleting B cells. The next question was “how do you get to a molecule that has good properties?” he said.
“The idea behind CLN-978 is that you have a CD19 binder with very high affinity, you have a CD3 binder, and you have a serum albumin binding domain [which] extends the half-life,” Grieshaber-Bouyer said.
This extended half-life is “actually critical,” he explained, as it allows CLN-978 to be administered subcutaneously rather than intravenously.
At EULAR, Grieshaber-Bouyer was able to show the world that CLN-978 causes “a better and better depletion of B cells” as the dose is increased, with “most patients that get a higher target dose reaching complete B cell depletion.”
“Based on this data set, which is still early, but is already rich enough, we can see a path towards what the dosing, and then ultimately an actual drug, looks like,” he said.
When it comes to proving that TCEs could really work to treat autoimmune diseases, “this is probably the most comprehensive data set that is available so far,” Grieshaber-Bouyer added.
One shadow over approved T-cell therapies has been adverse events like cytokine release syndrome (CRS). While between 30% and 35% of patients in Cullinan’s study have experienced CRS, these cases have been “almost exclusively grade 1,” Grieshaber-Bouyer said, describing this as a “very clean safety profile.”
The study is continuing to enroll patients and expanding into multi-dose cohorts, with more data to be read out soon. But for now, Grieshaber-Bouyer is happy that his theory is panning out.
“We had shown this as an academic, small, proof-of-concept study … and the hypothesis was if you set up a proper study with a next-gen compound [then] you will match and then exceed that in terms of depth of depletion and efficacy,” he explained.
“It's looking like this hypothesis will pan out,” he added.