NEW YORK – Seattle Children's this summer is launching the first clinical trial in the US to test the activity of an autologous CAR T-cell therapy against a common form of lupus in pediatric patients.
There is growing interest in assessing CAR T-cell therapies in systemic lupus erythematosus (SLE), a chronic autoimmune disorder. There are CAR T trials underway at Bristol Myers Squibb, Cabaletta Bio, Cartesian Therapeutics, ImmPact Bio, and Novartis Pharmaceuticals in patients with SLE, but they are all enrolling adults over the age of 18.
Physicians at Seattle Children's, however, are looking to bring a promising cell therapy approach to children with SLE and are ramping up plans to test the CAR T-cell candidate previously evaluated in cancer.
"We felt that pediatrics was an important population to treat," said Shaun Jackson, a pediatric nephrologist and rheumatologist at Seattle Children's and an associate professor of pediatrics at the University of Washington School of Medicine. About 1 in 10 adults with SLE are diagnosed when they are children, according to a population-based study published in 2021.
At Seattle Children's, investigators are awaiting approval from an institutional review board to launch the clinical trial but expect to open enrollment in July.
The CD19-targeting CAR T-cell therapy was developed on-site at the hospital system's nonprofit therapeutics arm, which advances cell and gene therapies for pediatric populations and is leading the clinical trial. Jackson is not an employee of Seattle Children's Therapeutics but will serve as the principal investigator on the Phase I study of the experimental cell therapy.
Currently, standard care for SLE involves a combination of medications to try to keep the disease controlled, and the specific cocktail of medications depends on a patient's symptoms, which can vary widely. For example, patients with lupus might take the antimalarial drug Plaquenil (hydroxychloroquine), corticosteroids, or immunosuppressants, among other medications.
But "despite the combination of therapies, there are a subset of patients that just don't respond, or they only have a partial response," Jackson said. "They have ongoing inflammation despite being on this combination of four or five drugs."
The concept behind experimental CAR T-cell therapies for lupus hinges on B cells, a part of the immune system that's dysfunctional in SLE patients. By targeting and depleting B cells, researchers hope that patients will see their SLE symptoms dissipate or disappear completely. In a clinical study of an autologous CAR T-cell therapy in Germany, eight SLE patients had sustained remission for more than two years after treatment, Jackson noted.
The ultimate hope, according to Jackson, is that after CAR T-cell therapy, SLE patients will sustain a state without disease activity and be able to taper off immunosuppressive agents they're taking.
Within the single-site Phase I trial, dubbed Reversing Autoimmunity Through Cell Therapy, or REACT-01, investigators at Seattle Children's expect to enroll 12 patients with refractory SLE, a progressive form of the disease that impacts major organ systems and isn't controlled by standard treatments.
Patients who may be a fit for the clinical trial, along with their caregivers, will meet with a nephrologist or rheumatologist to discuss the study protocol, as well as a member of the oncology team to learn more about the cell therapy.
Researchers will primarily be evaluating safety and feasibility of the cell therapy and will be monitoring outcomes like cytokine release syndrome and neurotoxicity. In addition, they'll be assessing whether patients achieve remission and for how long that remission lasts.
This CAR T-cell therapy is not the first such treatment to be advanced at Seattle Children's, which has been developing, manufacturing, and clinically testing cellular immunotherapies for childhood cancers since 2012. In 2020, the hospital system established Seattle Children's Therapeutics, which now has more than 100 employees, including staff focused on R&D, clinical trials management, and regulatory affairs.
With the CAR T-cell therapy for SLE, the therapeutics group has garnered the US Food and Drug Administration's clearance for its 17th investigational new drug (IND) application, but this is the first candidate therapy the team has developed outside of cancer.
It can take years to develop a novel therapy, said Colleen Annesley, medical director of Seattle Children's Therapeutics and an associate professor in the pediatric hematology/oncology division at UW's medical school. However, the process to develop the CAR T-cell therapy and design a study protocol for SLE was quicker, since researchers were building on years of previous work in leukemia and lymphoma. They were able to apply the cell therapy product, SCRI-CAR19, which they had already tested in those cancers, to the SLE indication. A manuscript with results from clinical trials investigating SCRI-CAR19 in leukemia and lymphoma is in the final stages of preparation for submission, and Seattle Children's Therapeutics plans to continue to test next-generation versions of SCRI-CAR19 in the cancer setting, Annesley said.
Because researchers were starting with a CAR T-cell product they had already studied in another setting and because Seattle Children's is well versed in manufacturing, regulatory requirements, and clinical trials, it took less than a year from when researchers began discussing a CAR T-cell therapy for SLE, to designing the study protocols and to getting an IND application approved by the FDA in March.
"We didn't have to start from scratch," Annesley said.
Mostly, Seattle Children's Therapeutics conducts first-in-human Phase I trials. The group has conducted two Phase I/II trials that have advanced into Phase II, testing cell therapies in relapsed and refractory B-cell acute lymphoblastic leukemia and lymphoma. However, for later stage studies, significant resources are necessary to manage larger patient populations across multiple sites.
The therapeutics division is open to partnering with biotech companies to advance its early-stage programs and to develop new cell and gene therapies, Annesley said. In one case, Juno Therapeutics, now part of Bristol Myers Squibb, licensed a CAR T-cell therapy for certain patients with large B-cell lymphoma from Seattle Children's. In 2021, that therapy was approved by the FDA as Breyanzi (lisocabtagene maraleucel), though only in adult patients. In the years since, Bristol Myers Squibb has continued to expand Breyanzi into other hematologic cancer indications.
If investigators in the Phase I REACT-01 trial observe promising outcomes, and it makes sense to advance into a Phase II trial, they may look for an industry partner to support continued development, Jackson said. Findings from the Phase I study could also underpin development of CAR T-cell therapies for other autoimmune diseases that are triggered by autoreactive B cells.
"There are a wide range of different autoimmune diseases where CAR T cells might be effective," Jackson said. "That's the exciting part from our side: to really try and expand how we think about these therapies and the benefits they could provide."