‘The stage is set’ for next generation of CAR T cells in rheumatology
Although chimeric antigen receptor T-cell therapy has delivered previously unthinkable remission outcomes to patients with lupus and other rheumatic diseases, the cells currently in use remain “old fashioned,” according to a speaker.
During a roundtable discussion at the Cleveland Clinic Basic and Clinical Immunology for the Busy Clinician symposium, Maximilian F. Konig, MD, of the Johns Hopkins University School of Medicine, stressed that the CD19 CAR T cells currently being administered were designed in the 1990s.
“They are old-fashioned designs, and they have not evolved that much,” he told attendees. “Additional engineering tricks will bring the T cells up to speed.”
Another issue is that the current T cells in use were designed for the oncology space. Meanwhile, research in the rheumatology space is, relatively speaking, just getting underway.
“It will take time to catch up,” Konig said.
Konig’s roundtable comments were in conversation with Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic.
As research into CAR T-cell therapy in autoimmune disease continues, Calabrese said he is optimistic that rheumatologists will be able to have conversations with their patients that they would not have believed possible even 5 years ago.
“I pinch myself to engage in this conversation,” he said. “We are talking about deep remission. This is something we had not dreamed of in this generation, and now we are actually seeing it.”
Konig stressed that the initial work in CAR T-cell therapy from the group led by Georg Schett, MD, “put the bar really high” in terms of expected outcomes.
“The bar is durable disease remission,” he said.
Biologic B-cell-targeting therapies like rituximab (Rituxan, Genentech) can deplete B cells in the peripheral blood, but are less efficacious at targeting them deep in the lymphoid tissue and bone marrow, according to Konig. Meanwhile, CAR T-cell therapy can eliminate B cells in those hard-to-reach places, he added.
“The stage is now set,” Konig said. “The goal is to achieve deep depletion with whatever product it is, and achieve this immune reset, meaning you are forcing a whole entire immune compartment to be repopulated by naïve cells that have no prior memory of causing lupus.”
The critical question is how best to achieve that “deep depletion.” Most of the current research has focused on depletion of CD19 B cells, but other targets, like B-cell maturation antigen (BCMA) — a target in multiple myeloma — have also entered the discussion, according to Calabrese.
“If we are accomplishing remission with CD19, do we need BCMA?” he asked.
In response, Konig argued that if a patient can achieve remission with a CD19 cell, “there is no reason” to pursue a BCMA-targeted approach.
“BCMA is broader, and therefore more toxic,” he said.
Other approaches may target T cells, CD4 or CD8 killer cells, according to Konig. However, the response with these targets may be variable.
“The ability to kill is not equal among all engaged cells,” Konig said. “It matters what you engage.”
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Roundtable discussion. Presented at Basic and Clinical Immunology for the Busy Clinician, Feb. 27, 2025; virtual meeting.
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