CAR-T cell therapy, recent approvals put precision medicine ‘on the horizon’ for lupus
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The recent success of chimeric antigen receptor-T cell therapy, along with three high-profile FDA approvals, may help make precision medicine a reality in lupus, according to a presenter at the Biologic Therapies Summit.
“It is prime time for biologic therapies and the treatment of lupus,” Emily Littlejohn, DO, MPH, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, told attendees.
Before 2011, there was a “pretty scant” array of therapies for lupus, according to Littlejohn. However, the period of time from 2020 to 2021 brought about a “lupus renaissance,” with the approvals of belimumab (Benlysta, GlaxoSmithKline) and voclosporin (Lupkynis, Aurinia) for lupus nephritis, and anifrolumab (Saphnelo, AstraZeneca) for systemic lupus erythematosus.
That said, these approvals have not yet necessarily translated to the clinic.
“We are still not doing a very good job,” Littlejohn said. “Our outcomes are not where they should be considering how many medications we have.”
However, the research community is at work. Increased understanding of disease pathogenesis — including involvement of B cells, the complement system, cytokines and chemokines, dendritic cells, plasma cells, T cells, and intracellular machinery — has provided myriad therapeutic targets.
According to Littlejohn, several novel medications that may soon make their way to the clinic include litifilimab (Biogen), interferon-alpha kinoid, iberdomide (Bristol Myers Squibb), obinutuzumab (Gazyva, Genentech), deucravacitinib (Sotyktu, Bristol Myers Squibb), ianalumab (Novartis) and CAR-T cell therapy.
Litifilimab is an IgG1 monoclonal antibody targeting dendritic cell antigen 2, according to Littlejohn. She suggested that the drug has shown promise in cutaneous lupus.
“It has great potential in the skin,” she said. “It is not as exciting for the joints.”
Conversely, interferon-alpha kinoid demonstrated some encouraging results in the joints in phase 2b trials but ultimately failed to meet its primary endpoint.
“The trial was terminated,” Littlejohn said. “Its future is uncertain.”
Moving to iberdomide, Littlejohn stated it has the capacity to degrade transcriptional factors Ikaros and Aiolos. This, in turn, may reduce B cell activity and type I interferon pathways. Although the drug met the primary endpoint of SRI4 response at 24 weeks, there were some concerning safety signals.
“There was lack of diversity in the trial,” she added. “Most secondary endpoints were not met.”
Rituximab is an anti-CD20 antibody medication that previously failed to meet endpoints in lupus. However, a recent trial with obinutuzumab, a similar anti-CD20 antibody, used in lupus nephritis showed that the drug may yield renal response through 52 weeks, and possibly through 104 weeks.
The TYK2 inhibitor deucravacitinib “has gotten a lot of press in psoriasis,” according to Littlejohn. Although it has shown efficacy in helping patients with lupus reach SRI4 response through 32 weeks, respiratory infections, urinary tract infections, headaches, rashes and acne have been reported.
Further afield is ianalumab, which targets the BAFF pathway.
“It has been difficult to find phase 2 data for this drug,” Littlejohn said. “Keep an eye on phase 3 trials.”
The future may be brighter for CAR-T cells, according to Littlejohn.
“The most exciting thing happening in lupus is CAR-T cells,” she said.
Although there is only one data set with five patients available for analysis, all participants experienced a complete remission of lupus nephritis. In addition, arthritis fatigue, fibrosis of cardiac valves and lung impairment disappeared after this intervention.
“Interferon alpha was undetectable in serum of these patients at follow-up,” she added.
Although Littlejohn underscored a “huge risk” for cytokine release syndrome associated with CAR-T cells, the efficacy results nonetheless inspire optimism.
“It is promising for our very sick lupus patients,” she said. “We are one step closer. Precision medicine is on the horizon for lupus.”
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Littlejohn E. Advances in biologics in lupus. Presented at: Biologic Therapies Summit X; May 11-13, 2023 (hybrid meeting).
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