Although rheumatologists consider chimeric antigen receptor T-cell therapy “potentially transformative,” nearly 70% remain hesitant on whether its efficacy outweighs the possible risks, according to survey data from Spherix Global Insights.
“We are standing at the threshold of major change in rheumatology,” Sawyer May, insights director of rheumatology at Spherix Global Insights, told Healio. “The survey data and clinical experience underscore genuine excitement about cell therapies’ potential to deliver drug-free remission — or even cure — for severe, refractory autoimmune diseases.”
Spherix surveyed 104 rheumatologists regarding several topics associated with CAR-T cell therapy, including ideal patient populations, risks and benefits, logistical and financial concerns, and directions for future research.
According to the report, 51% of rheumatologists have a “very favorable” view of the data released so far regarding the use of CAR T-cell therapy in rheumatic diseases, while another 47% percent are “somewhat favorable.”
However, when asked whether the efficacy of CAR T-cell therapy outweighs the potential risks, 68% percent answered with a resounding “Maybe.” For these providers, their ultimate answer would depend on the patient’s disease severity and the availability of other options, according to Spherix. Just 27% said they felt the efficacy currently outweighs the risks.
Still, rheumatologists in the survey expressed generally bullish views on these emerging therapies. Open-ended responses from participants included declarations that CAR T-cell therapy “shows strong potential as a transformative treatment for severe, treatment-resistant autoimmune diseases,” and may be “revolutionary.” Another response predicted it would “fundamentally change rheumatology.”
Dinesh Khanna, MD, MSc, Frederick G.L. Huetwell professor of rheumatology at the University of Michigan, and director of the University of Michigan Scleroderma Program, expressed similar hope. According to Khanna, who was not involved in the Spherix report, CAR T-cell therapy represents a “paradigm shift” in the specialty.
“Instead of lifelong immunosuppression, it offers the possibility of an immune reset with drug-free remission,” he said.
However, he cautioned this shift may not occur for some time.
“All current data are from a limited group of patients — mostly severe, refractory cases treated in phase 1 trials at highly specialized centers,” Khanna said. “Significant adverse events, including neurotoxicity, cytokine release syndrome and flares temper enthusiasm.”
Clinical concerns are not the only obstacles to CAR T-cell therapy’s future use in rheumatology, according to May.
“In my opinion, access remains the biggest question mark for how these therapies are ultimately integrated into clinical practice, if approved,” he said. “Manufacturers are testing performance-based contracts, among other schemes, to find a way forward to get these novel therapies covered.”
However, exactly how and when these therapies enter rheumatology practice may depend on the urgency felt among specific patient populations — and their providers.
‘The urgency of SSc’
According to the Spherix report, a plurality (44%) of rheumatologists are willing to adopt CAR T-cell therapy as a first-line or early treatment in systemic sclerosis. This was the only condition that demonstrated such a plurality, as just 27%, 26% and 24% of rheumatologists reported the same eagerness to use the treatment as a first-line for systemic lupus erythematosus, lupus nephritis and idiopathic inflammatory myopathies, respectively.
For Khanna, this is more of a comment on the lack of options in SSc than it is a comment on the utility and effectiveness of CAR T-cell therapy in this patient population.
“It makes sense that SSc stands out here,” he said. “Nearly half of rheumatologists would consider CAR T as a first-line or early treatment for SSc, reflecting just how limited our options are for this disease. While we have targeted FDA approved therapies for lung fibrosis and pulmonary arterial hypertension, no treatment targets overall disease progression in SSc. The disease is known for its high mortality, rapid progression and irreversible organ damage, leading clinicians to embrace potentially transformative options sooner.”
According to May, the data show SSc “probably has the lowest bar for CAR T,” with any patient a potential candidate before progressive damage sets in.
“This therapeutic gap is one reason rheumatologists may be more open to considering an early, high-intensity intervention such as CAR T-cell therapy in SSc,” he said.
Khanna said he has seen this scenario play out in the real world.
“In my own experience at University of Michigan’s large scleroderma center, we are already seeing greater interest and earlier referrals for cellular therapies, particularly for severe or refractory cases,” he said. “The urgency of SSc pushes clinicians toward innovation, while more established diseases see slower change.”
Meanwhile, May pointed to specific outcomes in SSc that may make it a more attractive target for cellular therapies.
“Among rheumatic conditions, systemic sclerosis has one of the highest rates of interstitial lung disease (ILD), and SSc-ILD is widely regarded as the most common cause of SSc-related death,” he said.
May added that although tocilizumab (Actemra, Genentech) and nintedanib (Ofev, Boehringer Ingelheim) are approved to slow the rate of pulmonary decline, clinicians still lack any therapy capable of meaningfully reversing fibrosis or restoring lung function.
“Notably, after this survey was fielded, Bristol Myers Squibb released phase 1 data from the Breakfree-1 trial showing that CAR T-cell therapy in SSc led not just to stabilization, but to improvements in lung function,” May said. “Beyond ILD, there are no therapies approved to treat SSc. This dearth of treatment options and high prevalence of ILD makes CAR T-cell therapy particularly intriguing to rheumatologists.”
Conversely, lupus and inflammatory idiopathy myopathies have the benefit of FDA-approved treatments. This may impact how rheumatologists view CAR T-cell use in those indications.
‘Very robust’ pipeline in lupus
According to the Spherix data, 56% of rheumatologists reported high concern for immune effector cell-associated neurotoxicity syndrome (ICANS) regarding CAR T-cell therapy, while 49% reported concerns about cytokine release syndrome.
“Physicians tend to weigh the risks and benefits more cautiously,” Khanna said. “Given this, most clinicians follow guidelines in exhausting safer, conventional options first, and would only pivot to CAR T in highly refractory or complicated cases.”
This preference is reflected in the Spherix data, which show that in SLE and lupus nephritis, most rheumatologists would reserve CAR T for second- or third-line use, or even later, only after approved therapies fail.
“This reflects the robust armamentarium we already have for these diseases, including biologics like belimumab (Benlysta, GlaxoSmithKline) and anifrolumab, and conventional immunosuppressives,” Khanna said.
Cost is also a concern for CAR T-cell use in lupus, according to May.
“Rheumatologists are largely aware that autologous CAR T is extremely expensive,” he said. “Biologics such as belimumab are comparatively less expensive and have a more favorable safety and tolerability profile. The late-stage lupus pipeline is also very robust with a variety of mechanisms of action targeting B cells, so many specialists will likely try a targeted biologic therapy before cell therapy.
“Meanwhile, there are concerns about the long-term side effects [of CAR T-cell therapy], as they are largely unknown,” May added. “There have been some reports of secondary malignancies in hematology/oncology associated with these types of treatment, but it remains unclear if there is risk in autoimmune disease.”
An additional concern for rheumatologists pertained to the durability of remission, according to May.
“If patients relapse after a few years, the calculus changes about whether the cost and risk justify the benefit,” he said.
Financial and logistical concerns also were top of mind for respondents to the Spherix survey.
Cost ‘will become critical’
According to Khanne, the cost of cellular therapy can range from $500,000 to $1 million per patient for the treatment of lymphoma, leukemia and other cancers, primarily due to the complex production and specialized care required.
“At present, these therapies are limited to clinical trials, so direct out-of-pocket costs are rare, but if CAR T moves into standard care, cost and reimbursement will become critical,” he said.
According to May, patient insurance and site-of-care will likely impact the exact cost for any given patient.
“Patient assistance programs will be vital for manufacturers,” he said.
Regarding site-of-care, May said academic medical centers are the most appropriate and feasible settings for administering CAR T-cell therapy — at least as far as rheumatologists are concerned.
“Currently in the United States, most oncology cell therapies are administered at specialized tertiary care centers, primarily academic medical centers,” May said. “These sites are equipped with the necessary multidisciplinary teams, including oncologists, ICU staff and neurologists.”
However, in the future, clinicians may be able to administer CAR T in an outpatient setting, which would reduce costs as well as burden on the patient, according to May.
“One hematologist/oncologist told us that managing CRS and ICANS requires specialized expertise, and that clear protocols will be needed to ensure emergency departments know whom to contact and how to intervene when these toxicities arise,” he said.
Ultimately, the financial viability of the approach will largely depend on efficacy, according to Khanna.
“On the bright side, if many patients achieve remission and return to productivity and no longer require lifelong medications, patients and society could see substantial savings in the long run,” he said.
However, to reach that point, providers will have to content with multiple logistical challenges involved in administering the treatment.
“Provision of CAR T requires highly specialized facilities for cell collection — apheresis — as well as inpatient monitoring, which often last 1 to 2 weeks for acute toxicity, and the expertise to manage complex adverse events,” Khanna said. “These facilities are well beyond those found in most community practice settings.”
To that end, the Spherix data provide one possible solution — results showed that 79% of rheumatologists support cell therapies that can be delivered in outpatient settings without preconditioning chemotherapy.
“This could lower barriers to adoption if manufacturers innovate beyond current inpatient protocols,” Khanna said.
However, more research is necessary to realize this protocol, he added.
“It is unknown if CAR T-cell therapy will be equally effective without preconditioning therapy,” Khanna said. “Right now, cellular therapies are part of phase 1 and 2 trials, typically restricted to the sickest patients at large academic centers, subject to strict eligibility criteria and trial enrollment limits. Wider launch will require streamlined regulatory approvals, expansion to community settings, and evidence for safe outpatient delivery.
“In the future, off-the-shelf therapy including allogenic CAR T and CAR-NK therapies, in vivo CAR, and T-cell engagers are likely to be more feasible in the community hospitals and clinic settings,” he added.
If those cell therapies are going to be used, a whole team of providers will be necessary to make it work, according to May.
“This quote from a qualitative interview we did with a hematologist/oncologist speaks well to this,” he said:
- “CAR T involves many people. At our center, it is performed by the transplant team, typically a hematologist-oncologist specialized in transplant or malignant hematology, and sometimes a radiation oncologist. We also rely on a case manager or nurse practitioner to handle pre-authorization, coordinate with the company for T-cell collection, shipment to the facility and the return of the CAR-T product for infusion. It’s a detailed process that requires extensive paperwork.”
For Khanna, broader adoption will depend on robust randomized controlled trials against current standards of care, as well as long-term data to answer “the big questions.”
“Can we achieve true long-term, drug-free remission? Are there unforeseen late toxicities? Only with this evidence can we confidently weigh benefit against risk for broader patient groups,” Khanna said.
Parallels to the introduction of rituximab (Rituxan, Genentech) may apply at the current moment, according to May.
“This was a transformative therapy that required years of real-world data to establish itself in rheumatology,” he said. “If future studies confirm durable, safe, cost-effective remission, cell therapy could fundamentally reshape autoimmune disease management. For now, cautious optimism — and a focus on rigorous evidence — are needed to get more insights on the cell therapy.”
