‘Huge surprise’: CAR-T cell therapy leads to remission in severe lupus
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Five patients with systemic lupus erythematosus achieved remission after receiving chimeric antigen receptor T-cell therapy, a result that could change the face of treatment for autoimmune conditions, according to researchers.
“It was a huge surprise, I have to say,” Georg Schett, MD, of Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, in Germany, told Healio. “We were excited from the beginning, and we continue to be thrilled by the response we observed.
“Of course, we are actually very happy to see that the approach is feasible in lupus, for instance that you can retrieve enough lymphocytes from an autoimmune patient to produce chimeric antigen receptor T (CAR-T) cells,” he added. “This has not been done before. Also, before the first patient, we did not know what would happen if you expanded T cells from an autoimmune patient and reinject them. We thought it might cause problems like inflammation, but that was not the case.”
Schett and colleagues explained the approach in the paper, which was published in Nature Medicine. According to the researchers, CAR-T therapy modifies some T cells involved in immune system functions, changing them into “rovers that can hunt the body for a certain target.” In lupus, the T cells were “set on the trail” of CD19, which is a protein on the surface of the B cells involved in disease flares, they wrote.
Four women and one man were included in the study. The median age was 22 years with a median disease duration of 4 years. These patients demonstrated severe, active SLE, with a median disease activity index (SLEDAI) score of 16.
Importantly, patients in this group were refractory to multiple immunosuppressive drugs. Clinicians transduced autologous T cells from patients with SLE with a lentiviral anti-CD19 CAR vector. The cells were expanded and reinfused into the patients at a dose of 1×106 CAR-T cells per kilogram of body weight after lymphodepletion with fludarabine and cyclophosphamide, according to the researchers. The CAR-T cells then expanded in vivo, depleting B cells.
The result was an improvement of clinical symptoms and normalization of lab parameters, which the researchers noted included seroconversion of anti-double-stranded DNA antibodies.
At 3 months’ follow-up, all five patients had reached SLE remission as assessed by DORIS criteria. The median SLEDAI score was 0 at this time point.
Drug-free remission was similarly maintained during a longer follow-up of 8 months. Remission continued even after B cells re-emerged at a mean duration of 110 days (standard deviation= ±32) after the CAR-T cell procedure, according to Schett and colleagues.
The researchers described the re-emergent B cells as “naïve,” with non-class-switched B-cell receptors.
The intervention was well-tolerated, according to the findings. Only “mild” cytokine-release syndrome was reported.
Schett sat down with Healio to discuss the study, the approach and how CAR-T cell therapy could change the face of the treatment of autoimmune diseases.
Healio: What made you examine CAR-T cell therapy for lupus?
Schett: Lupus is a very antibody-driven disease. It means there is a very strong activation of the B-cell system in lupus. The idea was to perform a treatment that eradicates the B-cell system thoroughly and allows resetting of the immune system. The CAR-T cell treatment approach comes from oncology, where it is necessary to completely eradicate malignant blood cells, such as in the treatment of leukemia and lymphoma. The tools to eradicate B cells in these diseases can be used in lupus.
Healio: You mentioned how surprised you were by the results. How about in terms of efficacy?
Schett: Yes, that was the second surprise. CAR-T cell therapy seems to be enormously effective. Lupus basically resolved within 3 months. Even more surprising, when the B cells came back after 100 days, the disease did not come back. Our concern was that when B cells came back, the disease may relapse, but that was not the case so far.
Healio: Was there concern during this 100-day period of B-cell depletion that the patients would be at risk for complications?
Schett: During the 100 days on average of B-cell aplasia, they have no antibody response to vaccines. That is clear. However, even if patients are vaccinated during B-cell aplasia, the response to vaccination is not zero. Nonetheless, it is recommended to vaccinate before CAR-T cell therapy, for example, if poor immunity is present against certain infectious agents, such as the coronavirus. This approach allows them to develop antibodies before they go into therapy.
Healio: Who might be good candidates for this intervention?
Schett: At the moment, good candidates are patients with severe lupus failing on conventional treatments. So far, we only have data for lupus patients. Whether other autoimmune diseases — meaning connective tissue diseases, such as myositis or systemic sclerosis — also profit from CAR-T cell therapy remains to be determined.
Healio: Could you talk about some of the safety outcomes that may occur with CAR-T cell therapy in lupus?
Schett: Safety is always a question of numbers of patients having been treated with a certain drug or intervention. The number of lupus patients who underwent CAR-T cell therapy in our study is very small, thus interpretations on safety of the procedure always need to be seen with caution. Two key safety aspects of this therapy, which we know from oncology, are cytokine release syndrome and neurotoxicity. These are frequent in leukemia and lymphoma patients treated with CAR-T cells but were absent or only very mild in our lupus patients.
Healio: Any thoughts as to why you did not see cytokine release syndrome or neurotoxicity?
Schett: There is a rather simple explanation. These toxicities are related to the total number of B cells in the body. The more B cells you have in the body, the more toxicities you may have. In a malignant disease, the total number of B cells is far higher than in an autoimmune disease. As lower overall numbers of B cells induce less CAR-T cell activation and less cell lysis, toxicities are also less frequent.
Healio: What is the potential impact of this approach for patients?
Schett: For patients, the impact is substantial. Many lupus patients have significant glucocorticoid exposure and are on continuous immunosuppression, especially if they are not getting into remission. After this treatment, patients could actually stop all these treatments. They receive a single CAR-T infusion and then they stop all other immunosuppressive treatments.
If the disease remains absent and patients do not have to take their drugs anymore, this is a huge improvement in quality of life. Patients reported their experience after CAR-T cell therapy, and told us that they were very relieved that they could stop the drugs and live a different, free kind of life.
Healio: How about the potential impact of this approach for practicing rheumatologists?
Schett: At present, CAR-T cell therapy is not approved for lupus, so it is not available on prescription. However, it opens the door for treatment of severe and refractory patients. Maybe 10% to 20% of lupus patients have severe disease and are not responsive to conventional therapies, which presents a huge therapeutic challenge. Given that many of these patients are young, you want to have something in your hands that allows to abrogate this disease. CAR-T cell therapy may give them a chance for long-term remission. However, it raises the need to identify the patients that profit most from such therapy.
Healio: Where can this treatment be done?
Schett: At the moment it can only be done through studies in dedicated centers where doctors are experienced in CAR-T cell treatment. Also, treatment it is expensive, and takes significant manpower. So, we are still a few years off from this being a routine therapy for SLE.
Healio: Could you talk about the utility of this approach in patients with less severe disease?
Schett: Patients with less severe lupus can generally be managed with currently available drugs. This is why we have started with critically ill patients, those who are at risk for kidney failure or dialysis, and that have failed on multiple treatments. However, as our learning curve increases, we may move to patients who have not necessarily failed at so many therapies.
Healio: What is the next step for this therapy?
Schett: We are doing a basket study next year where we look not only at lupus patients, but also at patients with dermatomyositis and systemic sclerosis. These are also diseases characterized by a severe course and B-cell involvement. If these efforts are successful, there could be strong argument for CAR-T cell therapy in a variety of the autoimmune diseases.
Reference:
Mackensen A, et al. Nat Med. 2022.doi:10.1038/s41591-022-02017-5.
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