CAR T-cell therapy may be a ‘miracle,’ but it is too soon to say ‘cure’
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It has been at least 2 years since the first cohort of patients with lupus underwent chimeric antigen receptor T-cell treatment, and, at least so far, for every one of them, each new dawn represents another day spent in full remission.
“All five SLE patients are in remission and drug-free,” Georg Schett, MD, of Friedrich-Alexander University, in Germany, whose lab produced the landmark 2022 study in Nature Medicine, told Healio Rheumatology. “All of them are now 2 years disease-free, and the first of them is now 3 years disease free.”
As the length of that remission grows, so too has the excitement within the rheumatology community — to say nothing of the number of conditions now slated as a potential target for CAR T-cell therapy.
Data on the treatment’s beneficial effects on autoimmune myositis, systemic sclerosis and myasthenia gravis have already been released. Meanwhile, researchers have administered first treatments in neuromyelitis optica and multiple sclerosis. According to Schett, other potential indications include rheumatoid arthritis, Sjogren’s syndrome, ANCA-associated vasculitis and blistering skin diseases.
These promising early data, and the breakneck speed with which additional trials have begun in myriad autoimmune diseases, have led many rheumatologists to begin nursing a feeling that is all too rare, at least in a field like rheumatology — hope for an actual, durable cure.
That said, there are just as many who are quick to temper the growing enthusiasm. Not all of the data have been positive, for example. During the EULAR 2024 Congress in June, representatives from Kyverna Therapeutics announced that a patient with lupus nephritis treated with its own fully human anti-CD19 CAR T-cell therapy, called KYV-101, experienced relapse after 5 months. The patient, one of 30 enrolled to receive KYV-101 across a range of autoimmune diseases, received a half-dose of 50 million cells and had initially demonstrated a response to the treatment.
“There was an early response, with decreased double-stranded DNA and elevation of complement levels, but by the 6-month time-point, those trends reversed,” James Chung, MD, PhD, chief medical officer at Kyverna, said during the press conference. “We don’t really know exactly what happened with this patient, but we do hypothesize that the low dose compared to the high BMI may have contributed.”
However, even aside from that single case of relapse, there are reasons to remain cautious. One reason is that targeting B cells has had a checkered past in rheumatology treatment.
“B cell depletion has always made sense as B cells make autoantibodies,” Michelle Petri, MD, MPH, professor of medicine and director of the Lupus Center at the Johns Hopkins University School of Medicine, said in an interview.
However, the highest profile B-cell depleting therapy, rituximab (Rituxan, Genentech) ultimately has not lived up to expectations, according to Christopher Palma, MD, ScM, director of the clinical research center and associate professor of medicine, allergy, immunology and rheumatology at the University of Rochester Clinical & Translational Science Institute.
“We have been down this road before when talking about B cells,” he told Healio Rheumatology. “I am always cautious when speaking about B cell approaches because rituximab did not pan out the way we hoped.”
Researchers have nonetheless remained undeterred, exploring other B-cell depleting medications such as obinutuzumab (Gazyva, Genentech), a comparable agent to rituximab with additional properties that may make it more effective than its predecessor. Meanwhile, some agents deeper in the pipeline promise to act on both B cells and T cells and deliver a comparable effect as CAR T-cell treatment.
“If the CAR T cells have an edge on account of being very effective at depleting B cells, then a molecule that is equally effective at depleting B cells should achieve the same results,” Ronald van Vollenhoven, MD, PhD, chair of the department of rheumatology and clinical immunology at the Amsterdam Medical Center, and director of the Amsterdam Rheumatology Center, told Healio Rheumatology.
The search is on for that molecule. The hope is to achieve the same results as those reported by Schett’s group, minus the cost and potential safety issues involved in CAR T cell therapy.
However, even if CAR T cells are likely to have a place in rheumatology care moving forward, there is still the question of patient selection.
“CAR T is not the right therapy for a wide scale of patients, but only for very severe patients,” Schett said.
It remains to be seen whether that calculus will change with advances in technology and more clinical trials in the rheumatology setting. In the meantime, all eyes are on the rapidly increasing number of studies in CAR T cell treatment in the rheumatology space.
‘A Miracle Occurs’
Feasibility of CAR T-cell treatment in SSc was reported in a 2023 case study published by Bergmann and colleagues in the Annals of the Rheumatic Diseases. The 60-year-old patient with severe, diffuse SSc underwent compassionate use treatment targeting CD19 cells.
Results demonstrated undetectable levels of ANA titers and SSc-specific antibodies after infusion. Analysis of clinical parameters showed a reduction in tender joint counts from 22 at baseline to three at 3 months follow up. Skin fibrosis also improved at this time point.
“There is increasing evidence to support the role of B cells in the pathogenesis of scleroderma,” Allen P. Anandarajah, MBBS, MS, of the University of Rochester Medical Center, told Healio Rheumatology. “Immunohistochemical reports have identified the presence of B cells along with other inflammatory cells in skin samples from areas of fibrosis. The frequency of B cells has also been shown to be higher in the peripheral blood of scleroderma patients compared to heathy controls.”
Anandarajah added that B cells are also known to activate fibroblasts.
“Additionally, a few trials have demonstrated that B-cell depletion with rituximab results in some improvements of clinical outcomes in patients with scleroderma,” he said. “Thus, it is not surprising that B-cell depletion with CAR T-cell treatment therapy is effective in scleroderma. It could become a viable option in the management of this disease.”
According to Petri, the depth of B cell depletion is the key to its success in conditions like lupus.
“A ‘miracle’ occurs,” she said. “When the B cells reconstitute there has been an immune reset to normal.”
Petri added that the findings in this case study are significant largely because scleroderma is “particularly challenging, as the fibrotic process cannot be reversed.”
Epidemiology may also present an argument in favor of the CAR T-cell approach in this patient population.
“Systemic sclerosis is an obvious place to use CAR T-cell treatment because of the high disease burden,” Palma said, adding that there are “few options” for these patients.
However, hope is growing for this patient population as more CAR T-cell data emerge.
In a paper published this year in the New England Journal of Medicine, Muller and colleagues evaluated a cohort of 15 patients, including eight with severe SLE, three with idiopathic inflammatory myositis and four with SSc who received a single infusion of CD19 CAR T cells. After a median follow-up duration of 15 months, DORIS remission was reported in all patients with SLE. Meanwhile, American College of Rheumatology-EULAR major clinical response was reported in all of the patients with myositis, and a decrease in EUSTAR activity index score was observed in each of the patients in the SSc group. All patients were able to cease immunosuppressive therapy.
“Like systemic sclerosis, refractory dermatomyositis has a high disease burden and few treatment options,” Palma said.
Clinicians and researchers alike have celebrated these findings.
“Mechanistically, it would be logical that CAR T cells directed at B cells, such as anti-CD19 cells, or against plasma cells like anti-BCMA, were effective for diseases that are driven in large part or entirely by pathogenic autoantibodies,” van Vollenhoven said. “This is true to varying degrees for many autoimmune diseases, and it is not always clear how much the autoantibodies that are found in those diseases do in fact contribute to the clinical manifestations. Myositis and systemic sclerosis are examples of diseases where autoantibodies are frequently found but their role is not unequivocal.”
The hope for CAR T-cell therapy in SSc and myositis is that certain subsets of these patient populations can be treated, but there is also hope that CAR T cells can have just as big of an impact in even rarer diseases.
From Wheelchair Dependency to Full Activity
In a paper published this year in Neuron, Motte and colleagues described treatment with autologous CD19-targeted CAR T cells in two patients with concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome. Results showed that both patients experienced “rapid clinical recovery and regained full mobility,” according to the researchers. Moreover, they reported “normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels” that were accompanied by neurological response.
Patients transitioned from wheelchair dependency to full activity levels within 2 months of infusion. One patient remained stable at 4 months post-infusion, while the other was stable 6 months out.
“Myasthenia gravis could be an attractive target for CAR T cell treatment, as well, given that it is a direct autoantibody disease,” Palma said. “The caveat there is that there are already effective strategies for managing myasthenia gravis.”
However, the list of potential targets does not stop there, according to van Vollenhoven.
“The most convincing disease where the antibodies are, so to say, to blame for the disease, are perhaps found outside rheumatology, such as Hashimoto’s thyroiditis and neuromyelitis optica spectrum disorder,” he said.
Palma added that the role of autoantibodies in ANCA-associated vasculitis may also make CAR T-cell treatment effective in that condition.
“There could be a huge number of potential diseases that would benefit from this approach,” he said.
Another of those diseases is multiple sclerosis.
“MS is a condition that impacts B-cell pathology and may provide a suitable target for CAR T-cell treatment,” Palma said.
Anandarajah additionally included IgG4-related disease and pemphigus vulgaris in the list.
However, among this excitement, research and data, there are certain safety outcomes that may prevent CAR T-cell therapy from reaching widespread use.
‘The Real Risk of Cellular Therapy’
Further findings from the Muller paper showed that grade 1 cytokine release syndrome occurred in 10 patients. In addition, grade 2 cytokine release syndrome was observed, along with grade 1 immune effector cell-associated neurotoxicity syndrome and pneumonia that resulted in hospitalization.
“Some cellular therapy side effects such as cytokine release and immune effector cell-associated neurotoxicity syndrome (ICANS) have been more rare and milder in SLE than in oncology, likely due to patients with SLE having fewer B cells,” Petri said.
Cytokine release syndrome may occur in as few as 5%, and as many as 75%, of cases of CAR T-cell treatment, according to Anandarajah.
“Common clinical manifestations of this syndrome include fever, headache, fatigue, myalgia, arthralgia, rash and diarrhea, while hypotension and multi-organ failure have been reported in severe cases,” he said. “ICANS is seen in about 10% to 40% of cases and is associated with neurological features varying from disorientation to coma.”
Other possible side effects of CAR T-cell therapy include transverse myelitis, Guillain-Barre syndrome and hypogammaglobulinemia.
“The latter can lead to an increased risk for infections,” Anandarajah said.
According to Petri, the FDA has also noted concerns about late T-cell lymphoma.
“But the real risk of cellular therapy is the risk for infection during the period of B cell depletion,” she said.
However, not all studies have found these risks. Granit and colleagues conducted a phase 1b/2a study of CAR T-cell therapy in a cohort of 16 patients with myasthenia gravis, and published the 2023 findings in Lancet Neurology. Results demonstrated no dose-limiting toxicity, cytokine release syndrome or neurotoxicity. Patients experienced some transient headache, nausea and vomiting that resolved within 24 hours of infusion. Moreover, improvements in Myasthenia Gravis Activities of Daily Living Scale, Quantitative Myasthenia Gravis score, and Myasthenia Gravis Composite score were observed, along with improvements in QOL parameters.
For van Vollenhoven, pretreatment with cyclophosphamide and fludarabine may be the most significant source of concern in CAR T-cell therapy.
“There are several points to consider,” he said. “While cyclophosphamide is used in severe autoimmune diseases, it comes with side effects and risks, such as immunosuppression, gastrointestinal intolerance and bone marrow suppression.”
The association of cyclophosphamide with irreversible ovarian failure and infertility should also be top of mind, according to van Vollenhoven.
“Fludarabine is not normally used for autoimmune diseases and therefore unknown to most rheumatologists,” he said. “I myself have only theoretical knowledge of its side effects and risks, but those are not negligible. Importantly, we cannot be certain that these pretreatments are needed for patients with autoimmune diseases, so we really do need studies to investigate this matter.”
As researchers continue to sort out and document safety data, the next consideration pertains to the ideal candidates for CAR T-cell therapy.
‘A Few Highly Selected Patients’
A significant number of patients with autoimmune diseases have severe complications.
“They do not respond to treatment and get their disease very early in life,” Schett said. “For these patients, CAR T cells are a very interesting option.”
However, for van Vollenhoven, the discussion of candidacy for CAR T-cell therapy breaks down into two questions.
“One question is if CAR T cells are a very effective option that can achieve remission in many patients after 3 to 6 months, then who would be an optimal patient?” he said. “The answer is a few highly selected patients with severe and refractory disease and a poor prognosis, but no advanced damage or comorbidities.”
However, if CAR T cells can indeed “make good on the promise” of putting autoimmune disease into a remission lasting longer than 2 years, without the need for any other treatment, then the situation changes radically, according to van Vollenhoven.
“Then, I think we would be inclined to use it for many patients with SLE and other diseases, probably the majority of those who have moderate or severe disease,” he said.
The questions surrounding patient selection naturally give way to another question being pursued in the research arena, which is the utility of B cell depleting strategies that do not carry the demands and risk of CAR T cell treatment.
‘Better B-Cell Depleters are Upcoming’
According to Palma, even if full CAR T-cell treatment is not applied on a wide scale in rheumatology, the ongoing slate of trials may lead to the discovery of another approach to B-cell depletion.
“Thinking maybe 10 to 20 years ahead, it is possible that a treatment with the same impact of CAR T-cell treatment will be developed that is cheaper, easier to produce and comes with less risk,” he said.
For his own part, Schett said he is inclined to agree.
“Alternative, better B-cell depleters are upcoming,” he said.
In a 2019 paper published in Nature Biotechnology, Choi and colleagues developed a “bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues.”
The CAR T BiTE cells secret EGFR-specific BiTEs that redirect CAR T cells and recruit untransduced bystander T cells against wild-type EGFR, according to the findings.
Several such bi-specific antibodies are being developed, or already in use for hematological indications, according to van Vollenhoven.
“These antibodies bind the B cell with one arm and T cells with the other, thereby priming the T cell to effectuate killing of the B cell,” he said.
Schett said he is encouraged by the science behind BiTE, but added that questions remain beyond the hematology-oncology applications.
“It remains to be determined whether these BiTE cells can achieve long-lasting, drug free remission in autoimmune disease,” he said.
Efforts are underway to explore this approach in rheumatology, according to van Vollenhoven.
In a 2022 paper published in the Annals of Rheumatic Diseases, Furie and colleagues investigated obinutuzumab, a humanized type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, in a cohort of 125 patients with lupus nephritis. According to the researchers, obinutuzumab bested placebo as assessed by complete renal response at weeks 52 and 104. Obinutuzumab also demonstrated efficacy in terms of other renal response measures, serologies, estimated glomerular filtration rate and proteinuria. No serious adverse events were reported for the study drug, and injection site reactions were comparable in both groups.
“Obinutuzumab is a B-cell depleting agent that has the same antigenic specificity as rituximab, but there are data suggesting that it penetrates lymphoid tissues better and thereby can achieve better B cell depletion,” van Vollenhoven said. “It had impressive results in phase 2 in lupus nephritis.”
However, further research is necessary to determine whether this could be widely applied in rheumatology.
“That is the big question, isn’t it?” van Vollenhoven said. “And the answer is: We don’t know.”
‘Exciting Time’
The original findings from Schett’s group should be cause for optimism, according to van Vollenhoven.
“The exciting thing about the very limited data with CAR T cells is that a few patients have now gone several years without further treatment and remained in complete remission without further treatment,” he said. “This has not been seen with other treatments, but it has also not been looked at in that way.”
There are some who argue that even if the CAR T-cell approach can be curative for lupus, lupus nephritis or other conditions, it is still too complicated and expensive to administer on a broad scale.
“I disagree,” Schett said, noting that kidney transplant, a year of hemodialysis or even newly approved medications to treat SLE are associated with significant cost. “CAR-T therapy costs $100,000 to $500,000, dependent where you will get it. Hence, only a few years of drug-free remission yield the break-even point.”
Experts like Anandarajah, meanwhile, would like to see more data before CAR T-cell therapy can be widely applied.
“It is a promising tool in the armamentarium to treat autoimmune disease but it is too early to speculate its use in clinical care,” he said. “In addition to toxicities mentioned above, cost considerations have to be taken into account. The discussion related to value and quality is tough.”
Although Anandarajah noted that the availability of new, effective treatments is always exciting for clinicians, initial use may be limited to refractory cases of autoimmune diseases.
“Moreover, one would anticipate costs to decrease with newer and improved methodologies to facilitate CAR T-cell treatment therapy,” he said.
In addition, clinical trials will be necessary to sort out issues with both CAR T-cell treatment and its successors.
“For CAR T cells, it will be interesting to see how trials will be conducted to assess efficacy, and how the FDA will determine approval,” Palma said. “There are currently no placebo-controlled trials.”
According to Schett, CAR T cells have been approved without a control arm in hematopoietic malignancies.
“As long as the autoimmune disease population studied in CAR T-cell studies will be severe, treatment-resistant patients, and as long as hard endpoints like drug-free remission are used, an open-label approach seems feasible,” he said.
The first and last question, then, becomes whether rheumatologists can begin talking about a cure.
“The findings from Dr. Schett’s group and others are extremely promising,” Palma said. “It may be premature to be calling this a cure, but it is certainly an exciting time. We do not often see this kind of excitement in the rheumatology space.”
- References:
- Bergmann C, et al. Ann Rheum Dis. 2023;doi:10.1136/ard-2023-223952.
- Choi BD, et al. Nat Biotechnol. 2019;doi:10.1038/s41587-019-0192-1.
- Furie RA, et al. Ann Rheum Dis. 2022;doi:10.1136/annrheumdis-2021-220920.
- Granit V, et al. Lancet Neurol. 2023;doi:10.1016/S1474-4422(23)00194-1.
- Motte J. Neuron. 2024;doi:10.1016/j.neuron.2024.04.014.
- Muller F, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2308917.
- For more information:
- Allen P. Anandarajah, MBBS, can be reached at 400 Red Creek Drive, Suite 240 Rochester, NY 14623; email: kelly_webster@urmc.rochester.edu.
- Michelle Petri, MD, can be reached at 601 North Caroline St., Floor 7, Baltimore, MD 21287; email: mpetri@jhmi.edu.
- Christopher Palma, MD, ScM, can be reached at 395 West St. Suite 007, Canandaigua, NY 14424; email: christopher_palma@urmc.rochester.edu.
- Georg Schett, MD, can be reached at Schloßplatz 4, Room 1.033, 91054 Erlangen, Germany; email: georg.schett@uk-erlangen.de.
- Ronald van Vollenhoven, MD, PhD, can be reached at Meibergdreef 9, 1105 AZ Amsterdam; email: r.vanvollenhoven@amsterdamumc.nl.
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