‘There is a whole other world out there’: Beyond CAR-T therapies for autoimmune diseases
Although chimeric antigen receptor T-cell therapy has raised hopes for long-term remission in autoimmune disease, it has several limitations that may be overcome instead through bispecific T-cell-engaging antibodies, according to a speaker.
“There is a whole other world out there that doesn’t require cell engineering and that allows us to maybe think about alternative strategies to tailor therapeutics to our patients’ needs specifically,” Maximilian F. Konig, MD, assistant professor of medicine at Johns Hopkins University, told attendees at the Cleveland Clinic Basic and Clinical Immunology for the Busy Clinician symposium.
CAR T-cell therapies have shown unprecedented efficacy in several autoimmune diseases, so far yielding several years of drug-free remission in lupus, rheumatoid arthritis and other conditions. However, the process — involving the collection of patients’ T cells, followed by multiple steps to genetically engineer and multiply them for reinfusion — is “quite a significant task,” Konig said.
He instead discussed an alternative that, like CAR T-cell therapies, first emerged from immuno-oncology — bispecific T-cell engaging antibodies. Describing them as “an antibody on steroids,” Konig said they consist of two arms: one that binds to a target cell, such as a B cell, and one that binds to an immune effector cell, such as a T cell.
“By doing that, this small protein is able to cross-link target cells and effector cells in a way that forces the creation of an immune synapse, activates the T cell and then kills the target cell,” he said. “So, without cell engineering, you now have the ability to treat B-cell driven diseases.
“In fact, these approaches using bi-specific antibodies have been so potent in immuno-oncology that they have really given CAR T-cells a run for their money,” he added.
Unlike autologous CAR T-cell therapies, a bispecific antibody would not involve any patient-specific preparation ahead of time and instead be considered “off-the-shelf.” Certain CAR-T methods, known as allogeneic, are also intended to be off-the-shelf, but none are FDA-approved.
However, these methods could present “a higher risk profile” compared with CD19-targeting CAR T-cell therapies, according to Konig. When researchers gave four patients with autoimmune diseases a bispecific antibody targeting BCMA on B cells and CD3 on T cells, there was a “significant signal toward hypogammaglobulinemia” shortly after treatment, he said.
“This is a significant downside of these therapies and probably a reason why they will remain primarily therapies that are applied to patients with most severe disease,” Konig added.
Konig outlined several potential ways bispecific antibodies could make the treatment of autoimmune diseases more precisely targeted, enabling the selective depletion of certain autoreactive B cells while leaving healthy B cells in place.
“You can probably keep the vast majority of the B cell compartment to enable potentially curative therapies without increasing the risk of infection,” he said. “If we can do this, maybe it can restore immune homeostasis in our patients at a much larger scale.”
Overall, immune effector cell treatment approaches, such as CAR-T, “are really changing the game in rheumatology,” but all currently have limitations, such as their resource-intensive nature or risks for infections and cytokine-related toxicities, according to Konig.
“I think it’s an opportunity to start dreaming and using the engineering tools we have available — both cell engineering and protein engineering — to maybe design for our patients the next generation of immunotherapies that are tailored to specifically the diseases,” he said. “Maybe if we’re doing this in a way that is successful, maybe we can get to disease control without increasing the risk of infection.”
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Konig MF. Advanced noncellular immunotherapeutics. Presented at: Basic and Clinical Immunology for the Busy Clinician: Special Series on CAR-T Cell and Advanced Immunotherapies for Autoimmune Diseases; Feb. 27, 2025 (virtual).