Small study, seismic implications: Exploring the promise, challenges of CAR T in lupus

Jan 15, 2024

It is not often that a single data set has the potential to fundamentally alter the treatment landscape for a disease in rheumatology, but recent findings on the use of chimeric antigen receptor T-cells in lupus may eventually do just that.

The study at hand was published by Andreas Mackensen, MD, Georg Schett, MD — both of Friedrich Alexander University Erlangen-Nürnberg, in Germany — and colleagues in Nature Medicine, and included five patients with lupus, including four women and one man.

“Our rationale was that systemic lupus erythematosus is probably the best example for a systemic B cell-mediated autoimmune disease,” Schett told Healio Rheumatology, explaining how it came about that CAR T cells were used in this group of patients in the first place. “Also, the high inflammatory activity in SLE and the progressive organ damage associated with this disease qualified it as first indication for CAR T-cell therapy.”

All five patients achieved SLE remission, according to the DORIS criteria, at 3 months follow up.

This result, and the accompanying paper that followed in Nature Medicine, sent shockwaves through the rheumatology community.

“The paper by Dr. Schett’s group is a provocative report of five SLE patients treated with CAR T CD19 therapy,” Anca D. Askanase, MD, MPH, director of the Columbia University Lupus Center, and professor of medicine in the division of rheumatology at the Columbia University College of Physicians & Surgeons, told Healio Rheumatology.

The approach “harnesses the power” of the patient’s cells, according to Askanase. She added that the 100% response rate in such a short duration demonstrates the possibility that this could truly be a game changer — if the results can be replicated on a larger scale. “Clinical symptoms resolve, antibodies disappear, and these are maintained for years after the treatment without the need for any additional medications,” she said.

It is difficult to overstate the importance of this finding, according to Allen P. Anandarajah, MD, professor in the department of medicine, allergy/immunology and rheumatology, and associate chair for wellness in the department of medicine, at the University of Rochester Medical Center, in New York.

“What we would like to do is reset the immune system,” he said. “This is the first study to show we may be able to do this in lupus.”

Meanwhile, Shivani Garg, MD, MS, director of the University of Wisconsin-Madison Lupus and Lupus Nephritis Clinics, and assistant professor in the rheumatology division at the University of Wisconsin School of Medicine and Public Health, described it as a “very interesting” paper.

“The timing is ideal,” she said. “Refractory lupus and lupus nephritis could increase the morbidity and mortality risk in young patients, and there is a huge unmet need in therapies for patients who fail current therapies.”

However, it is, after all, just one study — and a small one at that. Moreover, SLE is a highly complicated condition with myriad presentations and heterogeneity of both disease course and patient population.

There is much work to be done to understand the results of the current study and forge ahead to the next round of trials. In addition, it may be helpful to gaze back to previous experiences with CAR T cells in the hematology/oncology space for clues to what kind of safety and efficacy results could be expected in rheumatology.

Because it is just the one data set, experts have placed the findings from Mackensen, Schett and colleagues under a microscope for clues to future clinical trial design and findings.

The median age of participants in the study was 22 years (range, 6). They demonstrated a disease duration of 4 years (range, 8) and a median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of 16 (range, 8). In addition, the patients were refractory to multiple immunosuppressive drugs.

“It is still quite early to extrapolate the findings of this study for a few reasons,” Emily Littlejohn, DO, MPH, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, said in an interview. “The patients in this study were young patients with multi-organ disease, including lupus nephritis, and they all had positive lupus serologies with high SLEDAI scores.”

Study protocols called for autologous T cells from patients with SLE to be transduced with a lentiviral anti-CD19 CAR vector, according to the researchers. They were expanded and reinfused at a dose of 1 × 106 CAR T cells per kilogram of body weight following lymphodepletion with fludarabine and cyclophosphamide.

The cells “expanded in vivo,” the researchers wrote. When B cells were depleted, clinical symptoms improved, while laboratory parameters such as anti-double-stranded DNA antibodies were observed.

Further efficacy results showed that the median SLEDAI score after 3 months was 0 (range, 2).

The researchers additionally observed drug-free remission for 8 months (range, 12) after administration of CAR T cells. This remission persisted for a mean of 110 days (standard deviation ±32), even after B cells reappeared. When these cells did reappear, they were naïve and “showed non-class-switched B cell receptors,” the researchers wrote.

Despite the largely positive results, one lingering question about the study pertains to the persistence of the intervention.

“Long-term data is still needed to see if these patients stay in remission and monitor for any other side effects,” Littlejohn said.

In addition, although Garg is encouraged by the results, she noted the small sample size as well as the short follow-up duration.

“Overall, this study opens the gateway for larger clinical trials to examine the effectiveness of CAR T-cell therapy and its safety in managing refractory lupus, particularly refractory lupus nephritis, which is the need of the hour,” she said. “Additionally, studies are needed to identify the subsets of lupus population who will benefit most from this therapy.”

This seems to be the consensus among experts in the field.

“Until we have more data, it is difficult to apply these results to other types of patients with systemic lupus,” Littlejohn said.

Further data may, of course, offer further insight into the efficacy of this intervention. However, larger questions pertain to safety.

“Given what we know at this point, it is hard to say which lupus patients will be good candidates for CAR T-cell therapy, because, at the moment, the drug regimen is very toxic,” Anandarajah said.

According to safety data from the Mackensen study, all five patients demonstrated “mild” cytokine-release syndrome following treatment.

“The findings of this pilot study are intriguing as the results show a clinical reduction in proteinuria in patients with refractory lupus and overall mild cytokine release syndrome side effects from CAR T-cell therapy,” Garg said.

That said, it could have been much worse.

“Severe cytokine release syndrome or other severe side effects from CAR T-cell therapy seen in hematological disorders, were not seen in lupus in this study, which was reassuring,” Garg added.

Having seen the study up close, Schett also is encouraged by the lack of severe cytokine release syndrome and other adverse events.

“These are the key concerns of CAR T-cell treatment,” he said. “At the moment, tolerability of CAR T-cell therapy in autoimmune diseases seems to be good.”

However, for other experts, additional concerns remain. According to Anandarajah, CD20 cell depletion risk associated with immunization is the “most concerning” potential adverse event in future studies.

“However, this did not seem to be a problem in the five patients in Dr. Schett’s study,” he said. “In addition, some of the other toxic effects that we saw in hematology and oncology were not seen in those lupus patients, either.”

Infection risk is another of those “toxic effects” that Anandarajah mentioned.

In a paper published in Expert Review in Anti-Infective Therapy, Dizman and colleagues conducted a systematic review of 3,591 patients from 45 data sets that explored CAR T-cell therapy in relapsed or refractory B-cell malignancies and multiple myeloma. The overall infection rate was 33.8%, while serious infections were reported in 16.2% of patients. The pooled attributable mortality rate associated with these infections was 1.8%.

Anandarajah urged the research community to keep these infection rates in mind when investigating the approach in patients with lupus.

“Maybe down the road, we can figure out a less dangerous format of suppressing the immune system,” he said.

This study is just one of many that lupus researchers can use to guide safety protocols for CAR T cells moving forward. A closer look at that body of research may prove useful in the current discussion.

Hematology’s and oncology’s experiences with CAR T cells are legion and include a broad cross-section of adverse outcomes.

“In oncology, CAR T-cell therapy evolved rapidly and is now the standard of care,” Schett said. “We can follow this path if we want, if the results of this treatment remain excellent.”

Schett noted that CAR T-cell therapy in oncology also began with relapsing and resistant cases.

“But it later moved to high-risk patients as an early intervention, which could be foreseen also in autoimmune diseases,” he said, noting that patients with SLE as well as severe nephritis, rapidly progressing systemic sclerosis and MDA5-associated myositis all may be candidates.

As researchers wrestle with the optimal patient population, understanding some of the other events reported from the hematology/oncology experience is necessary. This includes neurological outcomes.

In a paper published in Immunotherapy, Gajra and colleagues aimed to characterize neurological adverse events associated with CAR T-cell therapy in a cohort of patients with refractory/relapsed large B-cell lymphomas. The analysis included 804 adverse events in patients treated with axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel). Results showed that 67% of patients in the axi-cel group and 26% of those in the tisa-cel group experienced neurological adverse events. Importantly, neurological events also carried associations with being aged 65 years or older and hospitalization, according to the findings.

Schett stressed that, in addition to cytokine release syndrome, immune effector cell-mediated neurotoxicity syndrome is the “key concern” with CAR T-cell therapy. However, he added that these neurological complications were not seen in the lupus cohort.

That said, there may be help in managing these outcomes. In an American Society of Clinical Oncology guideline document published in the Journal of Clinical Oncology, Santomasso and colleagues aimed “to increase awareness, outline strategies, and offer guidance” in managing immune-related adverse events (irAEs) associated with CAR T-cell therapy.

The range of outcomes covered in the document include not only cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, but also B-cell aplasia, cytopenias, and infections.

It is recommended that physicians use “supportive care” for many of these patients. For cytokine release syndrome, however, tocilizumab (Actemra, Genentech) with or without steroids is recommended. In addition, supportive care and corticosteroids may also be used for patients with neurotoxicity syndrome.

“The fact that the entire immunosuppressive medication can be stopped after CAR T-cell therapy is important for the long-term safety as infection risk may be substantially lower in the long run,” Schett said.

With that in mind, Anandarajah offered a starting point for the future.

“This is why we need to see much larger studies, to determine whether we can use this intervention safely in other lupus patients,” he said.

“Drug development will continue as usual,” Askanase said. “Phase 1, 2, and 3 studies need to be done to secure FDA approval.”

This is happening already. Kyverna Therapeutics recently announced that enrollment has begun for a phase 1 trial of their anti-CD19 CAR T-cell therapy KYV-101 for patients with lupus nephritis. The company in June stated that the FDA has granted fast-track designation for KYV-101.

That news followed on the heels of Cabaletta Bio’s CABA-201, another CD19-CAR T-cell investigational therapy for SLE and lupus nephritis, also receiving fast-track designation from the FDA. According to the company, Cabaletta Bio has received approval to initiate a phase 1/2 trial investigating the therapy in patients with SLE and lupus nephritis. The open-label trial will include two parallel cohorts of six patients each. One cohort will include patients with SLE without renal involvement, and the second will feature patients with SLE with active lupus nephritis.

Although she is excited for the potential of these and other future trials, Askanase stressed that the specific challenges of both lupus and the CAR T-cell intervention should induce caution in the research community.

“These may be different than the trials we have been accustomed to in SLE because of the very different nature of these therapies,” she said. “If indeed the efficacy is what we expect, once we define the appropriate lupus patient population, we should be able to provide answers quickly.”

Investigators are working on these answers.

In a paper published in the Journal of Allergy and Clinical Immunology, Doglio and colleagues offered a roadmap for the ongoing investigation of CAR T cells in lupus.

“Autologous hematopoietic stem cell transplantation has already provided the proof-of-concept that immunodepletion can lead to durable treatment-free remissions, albeit with significant treatment-related toxicity,” they wrote. “In the future, chimeric antigen receptor-T-cell therapies, for example, CD19 chimeric antigen receptor-T, may provide a more effective lymphodepletion and with less toxicity than autologous hematopoietic stem cell transplantation.”

Another approach is to enhance the immune system by “exploiting the suppressive capacities of regulatory T cells,” according to Doglio and colleagues.

“Different approaches have been developed in this area, from polyclonal to genetically engineered regulatory T cells,” they wrote.

These studies are likely to be conducted. However, the primary question — according to Garg — is who will benefit most.

“There is a need for therapies or treatments for patients with refractory lupus, particularly lupus nephritis,” she said. “This early study lays a foundation for larger studies that will test the effectiveness and safety of CAR T-cell therapy in patients with refractory lupus and lupus nephritis.”

Garg also stressed the importance of much larger studies with longer follow-up times.

“Additionally, data is needed regarding the disease course following cell repopulation after initial therapy over more than 3 months of follow up, to guide clinical use of this therapy in routine settings,” she said.

Looking deeper into the possible impact among patients with lupus nephritis, Garg argued that the change in proteinuria levels reported in the Mackensen study suggests that these patients may benefit.

“However, a key finding to note is that CAR T-cell therapy was directed against plasma blasts and not the long-lived plasma cells, which are CD19,” she said. “So, further studies are needed to identify the population who will benefit most from this therapy and if additional testing will be required to identify those groups.”

There is also the question of whether these studies into CAR T-cell therapy could — possibly, someday — lead to a cure for lupus.

“It is possible that CAR-T therapy will cure lupus,” Askanase said. “However, this therapy is not for everyone — the patients in the Schett paper had life-threatening lupus. Because of the heterogeneity of lupus, some patients may not benefit from it, and we will need to do the work to fully understand the safety and efficacy of CAR T in lupus patients.

“Several biotech companies have received clearance to proceed with the development of CAR-T products, and we and others are fully committed to do our part as investigators in these studies to bring these products to lupus patients,” she added.

What is known thus far is that the researchers in Mackensen’s and Schett’s group concluded that a CAR T-cell approach is “feasible, tolerable and highly effective in SLE.”

However, perhaps the most important question is whether CAR T-cell therapy may ultimately become standard of care in the lupus setting. Regarding this, Schett is optimistic.

“I do see a time when this will be the standard, as this has been already reached in the treatment of lymphoma and leukemia,” he said. “I do not see a reason why SLE and other systemic autoimmune diseases should be different. These diseases permanently change the life of patients and sometimes cause death. If we have a tool that cures them for their disease — like we see in cancer — we should develop and use it.”