Kyverna and Cabaletta are Repurposing CAR-T for Autoimmune Diseases
Peter Maag, CEO, Kyverna Therapeutics/company courtesy
Researchers at Kyverna Therapeutics and Cabaletta Bio hope to repurpose CAR-T cell therapy for patients with autoimmune diseases.
CAR-T cell therapy, or chimeric antigen receptor T cell therapy, is best known for its application in oncology, where the results have been life-changing for patients. Approved and experimental CAR-T therapies have resulted in reductions in death and progression of the disease and have jumpstarted remission in several malignancies.
This approach is applied in treating autoimmune diseases, chronic conditions in which the body’s immune system attacks healthy cells.
CAR-T cell therapy for autoimmune diseases made headlines in September 2022 when five patients with systemic lupus erythematosus (SLE) were confirmed to be in remission for an average of eight months after treatment. There were no signs of relapse in the first patient to receive the therapy after 17 months of follow-up.
The study, led by Friedrich Alexander University Erlangen-Nuremberg researchers, was published in Nature Medicine.
In autoimmune disease, the body produces autoreactive B cells, immune cells that produce antibodies against healthy cells and autoantigens, inviting T cells to produce an autoimmune response.
These autoreactive B cells are responsible for the symptoms and inflammation in patients with autoimmune diseases as they attack cells that perform essential bodily functions.
“Autoimmune disease is caused when a person’s immune system comes to see some part of the body as foreign; this is called ‘breaking tolerance,’” Gwen Binder, Ph.D., president of science and technology, Cabaletta Bio, told BioSpace.
She said this effect usually results from genetics, environment, general health status and infection history.
Once tolerance breaks, the proliferation of autoimmune reactions in the body begins.
CAR-T therapy can be beneficial as the therapy can specifically attack and deplete these autoreactive B cells within the body.
“Complete elimination of these autoreactive B cells in the blood and tissue reservoirs, something CAR-T cells can do but B cell-depleting antibodies cannot, could remove the central initiator and driver of autoimmunity,” Binder said.
CAR-T could offer a potential long-term solution to these chronic conditions.
Therapies Move Forward
Cabaletta is developing CABA-201, a fully human CD19 CAR containing a 4-1BB co-stimulatory domain.
Binder said the design of CABA-201 is similar to the one used in the German study where patients achieved remission.
Cabaletta’s fully human CD19 binder has demonstrated a favorable tolerability profile in approximately 20 patients. The 4-1BB co-stimulatory domain is associated with less frequent serious adverse events like cytokine release syndrome, Binder said.
CABA-201 is in preclinical studies for several undisclosed indications. It could target various autoimmune diseases, including SLE, rheumatoid arthritis and systemic sclerosis.
In Emeryville, California, Kyverna is developing KYV-101 for lupus nephritis. The FDA cleared the Investigational New Drug application for the CAR-T therapy in November 2022.
Peter Maag, Ph.D., CEO, told BioSpace that while other treatments for lupus show a 20% improvement over baseline, with multiple CAR-T therapy studies, he's seen a 100% complete response.
KYV-101 maximizes B cell depletion while minimizing cytokine release to avoid adverse events during CAR-T treatment. The release of cytokines can also be detrimental in an autoimmune environment.
In preclinical studies, CD19-targeted CAR-T cell therapies have demonstrated complete B cell depletion in circulation and tissues.
It’s too early to know how effective CAR-T cell therapies will be for patients with autoimmune diseases.
If a one-time administration of CD19-CAR-T can deplete all of the B cells in the body, Binder said it’s possible to reset the immune system and conceptually cause “long-lasting disease remission off therapy.”
More robust datasets are needed; however, CAR-T may not work in all cases.
Maag said that without long-term data, it’s impossible to tell how long the remission might last. But he reiterated Binder’s contention, saying CAR-T is “a complete resetting of the immune system for a substantial amount of time,” something that has never occurred in the autoimmune space.
As cell manufacturing costs decrease and the potential to scale increases, Maag said now is the perfect time to design CAR-T therapies against autoimmune diseases.
But the time is also ripe for those suffering from autoimmune diseases to experience innovative treatments that address their concerns.
“Patients can benefit from participating in a clinical trial,” he said.