Chimeric antigen receptor (CAR) T-cell therapy has cleared another hurdle on the path to potentially becoming a viable treatment option for people with severe autoimmune diseases, following the recent results from several open-label, nonrandomized phase 1 and 2a basket trials. Findings on safety from a study published in Nature Medicine and a pair of trials presented at this year’s recent Transplantation & Cellular Therapy Tandem Meetings suggest that adverse events from CAR T-cell therapies are mild-to-moderate and self-resolving in patients with a variety of autoimmune conditions.

Both agents — zorpocabtagene autoleucel (Zorpo-cel, formerly MB-CART19.1) from Germany-based Miltenyi Biomedicine and zolacabtagene autoleucel (Zola-cel, formerly BMS-986353) from Bristol Myers Squibb — are autologous CD19 agents tested in populations with systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies (IIM), relapsing multiple sclerosis, progressive multiple sclerosis, or myasthenia gravis. Across the trials, the two primary safety concerns of interest, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), occurred at acceptable rates with no severe cases, and events resolved within a few days on their own.

Disease activity meanwhile substantially improved across all patients without a need for continuing disease-specific medications.

“The major bridge through in this entire endeavor is that, for the very first time in severe autoimmune diseases, you actually have a treatment-free period,” Fabian Müller, MD, a senior attending physician and head of the CAR T-Cell Unit at University Hospital Erlangen in Erlangen, Germany, told Medscape Medical News. Müller is an investigator in both the Zola-cel and Zorpo-cel trials. “That is really a new perspective that has never been achieved before.”

Longer term follow-up will reveal how durable that result is, said Ren Reshef, MD, director of the Cellular Immunotherapy Program at Columbia University Irving Medical Center in New York City, who presented the results from Zola-cel.

“It’s still unclear how this treatment would affect the T-cell component or any other arm of the immune system that might be involved in pathogenesis [of the disease], but the proof is ultimately in the pudding, and what we’ve seen so far over several years of giving CAR T cells is a tremendous success,” Reshef said. “There have been no serious feasibility issues in making the cells, manufacturing the cells, taking patients off their therapies, and giving them CAR T therapy off immune suppression. The fact that they remain off therapies is already another indication for treatment success.”

CAR T cells have been an approved treatment for several hematologic cancers for nearly a decade, but they have only more recently been investigated for autoimmune disease.

“What sets apart CAR T-cell therapy is that it is capable of completely eliminating every B cell in the body until we reach a state of B-cell aplasia,” Reshef said. When the body then replenishes the B cells from scratch, “you are basically resetting the immune system” without repeating whatever initially caused the development of autoreactive B cells, ideally resulting in a durable and possibly permanent resolution of symptoms, Reshef said. “We are giving the body a second chance.”

Zola-cel expresses the same CAR as lisocabtagene maraleucel but has a shorter manufacturing period, which means better scalability and more potent cells with greater proliferative potential, expanding mostly in the body instead of the culture dish, Reshef said.

The response in the rheumatologic community to these developments has been a mixture of excitement and overwhelm, according to Elena Schiopu, MD, a professor of medicine and director of clinical trials at Medical College of Georgia at Augusta University, Augusta, Georgia, who was not involved with these trials. When the first results of early CAR T-cell therapy trials in patients with lupus were initially reported several years ago, it “felt like something close to the next revolution,” Schiopu told Medscape Medical News, reminding her of when the first TNF inhibitors were approved. “The results were just phenomenal. That was probably the most significant development we’ve seen since the big biologic step.”

The biggest draw for the therapy is that it’s a “one-and-done,” she said, but the space is also moving so quickly right now that it’s hard to keep up, particularly as the therapy is explored for multiple different autoimmune diseases.

Well-Tolerated Safety Across Trials

In the trials presented at the Tandem Meetings, Breakfree-1 assessed Zola-cel in 26 patients with lupus, 25 patients with systemic sclerosis, and 14 patients with IIM while Breakfree-2 included six patients with relapsing multiple sclerosis, nine patients with progressive multiple sclerosis, and three patients with myasthenia gravis.

The 83 patients were a median 44 years old and mostly White (68.7%) women (74.7%). They had active inflammatory disease with a median of two to seven prior failed treatments, depending on the condition. After leukapheresis, participants stopped all immunosuppressive medications and then received an autologous CAR T-cell infusion at a dose of 10 × 10⁶ cells for lymphodepletion.

“All patients achieved robust CAR T-cell expansion and complete peripheral B-cell depletion after Zola-cel infusion,” Reshef said. The median time to B cell repopulation was 113 days, with predominantly naive repopulated B cells.

Across both Breakfree trials, CRS occurred in 57.8% of participants with a median 7.5 days to onset. It was mostly grade 1 (48.2% of total participants) and it resolved in a median 3 days. There was one grade 3 case of CRS that was treated with tocilizumab and corticosteroids and resolved within 1 day. ICANS occurred in 12% of patients, was also mostly grade 1 (7.2%), and similarly resolved in a median 3 days. The three grade 3 ICANS events were treated with corticosteroids and anakinra and resolved within 3-5 days.

Over a median 92 days of follow-up, just over half the patients (53%) experienced any hematologic adverse events, most of which were cytopenias. Neutropenia and anemia were among those that were grade 3/4, but all resolved fully, as did the grade 3/4 infections that occurred in 6% of patients. There were no CAR-related malignancies.

Nearly all participants (91.6%) remained off disease-directed treatments at last follow-up, approximately 18 months after treatment.

Participants in the phase 1/2a CASTLE trial of Zorpo-cel had even fewer adverse events of interest and showed similar improvements in disease activity. The trial enrolled 10 patients with lupus, nine with systemic sclerosis, and five with IIM. The mostly female (71%) patients were a median 39 years old with a median 4 years of disease and a median three to six previous failed therapies.

The participants all received a single infusion of Zorpo-cel after stopping immunosuppressive treatments and undergoing standard lymphodepletion with cyclophosphamide and fludarabine. Prednisolone was used in 58.3% of patients as the only bridging treatment between stopping immunosuppressive treatments and receiving Zorpo-cel infusion. One patient with lupus experienced grade 3 organ toxicity after leukapheresis and stopping immunosuppression, but they were stabilized, underwent infusion, and recovered. Duration for B-cell aplasia was a median 83 days after infusion.

CRS occurred at grade 1 in 70.8% of patients and at grade 2 in one patient at a median 1 day after infusion and resolving after a median 3 days. Just over half (58%) of the patients received tocilizumab for CRS, and 17% received dexamethasone. No cases of ICANS occurred, and no clinically relevant neutropenia or thrombocytopenia lasted past 28 days.

All eight participants in the phase 1 stage of the trial met the secondary clinical efficacy endpoint of remission in patients with lupus, a moderate or major response in those with IIM, and no progression of lung disease in those with systemic sclerosis. In the phase 2a stage, 14 of the 16 participants met the clinical efficacy endpoint. One patient with IIM did not meet the criteria for adequate improvement in muscle strength, and one patient with lupus did not have enough reduction in proteinuria but did remain off lupus medications.

Long-Term Safety Surveillance and FDA Perspectives

Although long-term toxicities associated with CAR T-cell therapy in cancer treatment have included Parkinson’s disease, enterocolitis, motor and neurocognitive toxicity, and secondary cancer, the first three of these apply only to CAR T-cell therapy directed against B-cell maturation antigen (BCMA), not those directed against CD19, Müller explained.

The FDA generally requires a minimum 15 years of follow-up for all CAR T-cell therapy trials, and that will include surveillance for risk of malignancies, which remains an open question, he said. Some data has suggested that the chronic inflammation that occurs in these diseases induces T-cell dysfunction that means patients with autoimmune diseases already have an increased risk of cancer, so it’s possible that removing this inflammation with CAR T-cell therapy may “actually reduce the cancer risk,” Müller said.

“We need long-term data to compare patients with standard treatment and an active autoimmune disease to our CAR T-cell treated patients,” he said.

Another potential concern that requires follow-up surveillance is potential effects on fertility, including from the chemotherapy used prior to CAR T-cell infusion. Müller said some trials are experimenting with reductions in chemotherapy used to see if the response after infusion remains durable. That said, there have already been a couple healthy pregnancies and births in patients with autoimmune disease from earlier CAR T-cell therapy trials, Müller said.

In a commentary recently published in Annals of Internal Medicine, Anam Tariq, DO, of the FDA’s Center for Biologics Evaluation and Research and two colleagues laid out the agency’s perspective on evaluating CAR T-cell therapy for autoimmune disease, including encouraging industry to primarily focus on patients with refractory disease who have failed at least two immunosuppressive treatments besides steroids or hydroxychloroquine. But the agency also acknowledged the challenge in that definition for patients with severe disease “because of the high risk for irreversible organ damage with recurrent relapses and limited available treatment options” and therefore wrote it would “work with manufacturers on a case-by-case basis to encourage appropriate study populations in rheumatologic autoimmune disease.”

Müller agreed that identifying the right candidates for these treatments is a critical question.

“The patients that are amenable for cell therapy, because of the unknown side effects, are really the severe, life-threatening cases where end-organ damage is expected to happen soon,” Müller said. At the same time, “we think we shouldn’t do it too late in the disease history because, if you have too much end-organ damage already, some of it is not [reversible].” It’s a bit of a Goldilocks problem in identifying severe, refractory cases but without too much irreversible organ damage.

Tobias Kampfenkel, MD, a hematologist and medical oncologist who is vice president of Early Clinical Research & Development and Translational Medicine at Miltenyi Biomedicine, told Medscape Medical News that what the FDA shared “is very much aligned with our expectations and opinions.” Preliminary findings suggest the treatment is “well-tolerated with wonderful efficacy,” Kampfenkel said. “This is a transformative medicine, but you want to know what’s happening in the longer term,” including what signals to look for. “We need to align industry, regulators, academia, patients — all groups,” he said. “Our mission now is move this further and make it available in the future, based on pivotal, informative study data, in alignment with regulators, to as many patients with autoimmune disease as possible.”

The FDA authors also noted the challenges of relying on traditional assessments of disease activity used for other drugs and biologics for evaluating clinical response to CAR T-cell therapy, with interests in also looking at quality of life improvements and long-term, drug-free remission.

“To address these concerns, the FDA will work with patients, disease experts, industry, and other stakeholders to better define composite end points of clinical remission, immunologic remission, and/or validated treatment to target end points,” the FDA authors wrote.

Another issue the FDA will likely need to address in evaluating CAR T-cell therapy trials is that many participants are not based in the US. Given how likely it is that autoimmunity is at least partly influenced by environmental factors that may vary from one country to another, Schiopu is interested to see whether the agency requires a certain minimum percentage of trial participants to be from the US for approval, an issue the agency has already begun addressing in other areas.

The Breakfree trials were funded by Bristol Myers Squibb, and the CASTLE trial was funded by Miltenyi Biomedicine.

Reshef reported serving as a consultant or being in advisory roles for Allogene, Autolus, Bayer, CareDx, Gilead, Incyte, Orca Bio, Pierre Fabre Pharmaceuticals, Sail Biomedicines, Sana Biotechnology, Sanofi, and TScan and receiving research funding from AbbVie, Allogene, Arcellx, AstraZeneca, Atara Biotherapeutics, Bristol Myers Squibb, Cabaletta, CareDx, Genentech, Gilead Sciences, Immatics, Imugene, Incyte, Johnson and Johnson, Kinomica, Sanofi, Sonoma Bio, Synthekine, Takeda, TScan, and Vittoria Biotherapeutics. Müller reported receiving research funding from AstraZeneca, Bristol Myers Squibb, Gilead, and Miltenyi Bioscience and receiving consulting or speaking fees from AbbVie, AstraZeneca, ArgoBio, BeiGene, Bristol Myers Squibb, CRISPR Therapeutics, EcoR1, Incyte, Janssen, Gilead, Miltenyi Bioscience, MSD, Novartis, Pfizer, Sobi, and Takeda. Kampfenkel reported being an employee of Miltenyi Bioscience. Schiopu reported receiving research grants from Johnson and Johnson, Bristol Myers Squibb, Novartis, Galapagos, Argenx, Boehringer Ingelheim, Priovant, Horizon/Amgen, Biogen, and SetPoint; receiving consulting fees from Mediar Therapeutics; and receiving speakers fees from Johnson and Johnson.

Tara Haelle is a science/health journalist based in Dallas.