B-cell system reset in CAR T-cell therapy ‘feasible,’ leads to durable remission in lupus
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In patients with systemic lupus erythematous, CAR T-cell therapy appears to be a feasible and effective method of achieving durable remission, according to a speaker at the Biologic Therapies Summit.
“Lupus patients often need quite substantial amounts of glucocorticoids to stay in remission, and that is a huge problem,” Georg Schett, MD, of Friedrich-Alexander University, in Germany, told attendees at the hybrid meeting. “These are usually young patients and glucocorticoid use, in the long run, has substantial side effects.”
CAR T-cell therapy has recently shown promise in the lupus space, demonstrating benefits in patients who might not have seen impactful results from other therapies intended to push lupus into remission, Schett said.
The first patient to receive CAR T-cell therapy for lupus was a 20-year-old female patient who had already been treated with hydroxychloroquine, mycophenolate, tacrolimus (Prograf, Astellas Pharma), cyclophosphamide, belimumab (Benlysta, GlaxoSmithKline) and rituximab (Rituxan, Genentech), Schett said.
“It has been extremely disappointing, that rituximab, in randomized controlled studies, failed in lupus,” Schett said. “Rituximab is probably the only drug in the world that is not approved for lupus, and has negative studies, and is still used in lupus.”
Once the CAR T cells were cultivated, about 50 million were taken for use in therapy, while the rest of the cultivated cells were frozen, Schett said. The therapy cells are then infused into the patient over a short, 10-minute infusion.
“We were not sure whether the expansion of T cells from an autoimmune patient, also containing autoimmune T cells, would create a massive reaction in the patient,” Schett said. “These CAR T cells massively expanded from 0.3% being CAR T cells, to one-third of all T cells in the patient being CAR T cells after day 9.”
Following day 16, there was a “massive” reduction in the quantity of CAR T cells, Schett said. However, in following months, CAR T cells remained measurable circulating in the patient.
“They did their job,” Schett said. “And their job was to kill the B cells.”
Sometime between 50 and 150 days, Schett said, the B cells returned. However, the result was not a full return of disease, as is the case in lymphoma, but a “reboot” of the B-cell systems.
“What we did was reboot these B cells into a so-called ‘baby B-cell system,’” Schett said.
The result of the reset, he explained, is sustained remission through 18 months in some of the patients included in the early testing.
“Patient one is now more than 2 years in remission with no treatment,” Schett said.
Regarding tolerability and safety signals, Schett recalled that oncology patients receiving CAR T-cell therapy experienced cytokine surges.
“This happened at a very, very low level,” Schett said. “A key lesson here is that this is feasible.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
CAR T-cell immunotherapy for cancer has been developing since 1960, when scientists showed that immune cells in mice could kill cancer cells. The following year, T cells were discovered. In 1993, the first generation of chimeric antigen receptors (CARs) fused to part of an immunoglobulin were engineered. In 1998, the addition of the costimulatory molecule (CD28) was shown to prolong the life of the CARs in the circulation. In 2002, the first CAR T cells were developed and shown to survive, proliferate and kill prostate cancer cells in the lab, establishing the feasibility of CAR T-cell therapy.
A seminal paper was then published the following year demonstrating that human CD19-directed CAR T cells can kill leukemia cells in a mouse model. By 2013, clinical trials in humans were published using CAR T-cell therapy in cancer, while Science magazine proclaimed cancer immunotherapy the “breakthrough of the year,” and the FDA designated CAR T-cell therapy to have “breakthrough status.”
In 2017, the FDA approved CD19-directed CAR T-cell therapy for the treatment of relapsed, refractory acute lymphoblastic leukemia in children and young adults. There are now six FDA-approved CAR T-cell therapies in the United States — for six different cancers. The therapies have revolutionized the treatment of certain B-cell leukemias, lymphomas and other blood cancers, putting many patients who otherwise had little hope into long-term remission.
Attention is now being directed to autoimmune disease. The talk on CAR T-cell therapy for systemic lupus erythematosus at the Biologics Summit this year by Georg Schett, MD, was first published in Nature Medicine, as a breakthrough treatment for refractory SLE, in September 2022. Dr. Schett discussed how current anti-B cell therapy — rituximab (Rituxan, Genentech) — leads to a marked decrease in circulating B cells but not to depletion of tissue B cells. CAR T-cell therapy was highly efficacious for five patients treated by his group who had failed traditional treatment.
The first treated case was presented in detail — she had active lupus with 4 to 6 grams of proteinuria, highly positive anti-ds DNA antibodies, and had failed hydroxychloroquine, mycophenolate, tacrolimus, cyclophosphamide, belimumab (Benlysta, GlaxoSmithKline) and rituximab. Treatment with CAR T cells targeting B cells led to normalization of C3 and C4 complement, complete disappearance of anti-ds DNA antibodies, and complete resolution of proteinuria.
She is now 600 days post CAR T-cell therapy and is in remission with normal C3, no anti-ds DNA antibodies, no proteinuria, SLEDAI 2K of 0, and currently receiving no treatment. The Schett group has shown that after 100 days, when B cells reappear following CAR T-cell therapy, they are naïve B cells.
This entire scenario is an amazing result that needs a larger cohort to confirm and is very exciting for those of us dealing with intractable lupus patients. Lupus could be just the start of CAR T-cell therapy in rheumatology.
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