ѻý

Is Cancer Therapy Also a Lupus Cure?

<ѻý class="mpt-content-deck">— Patients in pilot study show months-long complete remission
MedpageToday
A computer rendering of a chimeric antigen receptor spanning the cell membrane of a T-cell

Autologous chimeric antigen receptor T-cell (CAR-T) therapy, an approach that has taken the oncology world by storm in recent years, could also revolutionize treatment for systemic lupus erythematosus (SLE), preliminary results in a handful of patients suggest.

Among five patients receiving a single dose of CAR-T cell therapy, all five achieved remission within 3 months, according to Georg Schett, MD, of Friedrich Alexander University Erlangen-Nuremberg in Germany, and colleagues.

Furthermore, all five remained in remission without need for other medications through follow-up of up to 12 months after the treatment, the researchers .

"[T]hese data provide new therapeutic possibilities to control SLE disease activity through engineered autologous cells," Schett and colleagues wrote, while noting that the treatment needs to be tested in more patients followed for longer periods.

CAR-T cell therapy involves extracting a patient's T cells via leukapheresis and, with the aid of viral vectors, transforming them to express receptor proteins that bind to a specific antigen on other cells that need to be eliminated. These transformed T cells are then reinjected into the patient, where they hunt down and kill the target cells.

For lupus, and for most forms of cancer as currently applied, the target is B cells. Oncologic indications at present include hematologic malignancies involving rogue B cells such as lymphoblastic leukemia and non-Hodgkin lymphoma. The treatment leads to "deep depletion" of B cells such that when the populations recover, they assume normal activity. (Efforts are also underway to find applications to other targets and solid tumors.)

Since B cells play a strong role in SLE, the idea that CAR-T cell therapy could be effective in this disease was picked up by a number of research groups around the world. And last year, Schett's group that the treatment helped a 20-year-old woman achieve complete remission in about 1 month, after she had failed to respond to virtually every other available therapy, including the anti-B cell drug rituximab (Rituxan).

That experience emboldened the researchers to try the approach in additional patients. In the current study, the patients were all very young (ages 18-24) and four of the five were women. Their baseline scores on the SLE Disease Activity Index-2K (SLEDAI-2K) ranged from 8 to 16 (on a scale of 0-105). All had skin and kidney involvement, four with joint symptoms as well. Belimumab (Benlysta) had been tried unsuccessfully in all five, as had corticosteroids, hydroxychloroquine, and mycophenolate mofetil. Other drugs used in some of the patients included rituximab, cyclophosphamide, and azathioprine.

Each patient underwent the T-cell extraction with ex-vivo transformation to target the CD19 antigen on B cells, plus a lymphodepletion regimen with fludarabine and cyclophosphamide. The CAR-T cell dose was 1 million cells per kilogram of body weight. In 1 week or less, B cell counts in all five patients fell to zero and stayed there through day 30. Counts of other immune cells also plummeted but then rebounded in 2-3 weeks.

As Schett and colleagues hoped, virtually all signs of lupus activity disappeared. SLEDAI-2K scores assessed 3 months after dosing fell to zero in four patients, reaching 2 in one patient whose baseline score was 16. Proteinuria vanished as well.

Perhaps most importantly, antibodies to double-stranded (ds) DNA also went to zero in all five patients. "While autoantibodies against dsDNA usually also decrease by conventional therapy, seroconversion is infrequent. All patients in our study seroconverted, lost dsDNA antibodies and showed decreases of levels of other SLE-associated antibodies," the researchers crowed.

B cell populations did eventually recover in line with decreases in CAR-T cell counts, but this was not accompanied by any recurrence of SLE symptoms or biomarkers, including anti-dsDNA antibodies.

Adverse effects related to the treatment were mild to non-existent. Cytokine release syndrome (CRS) and an associated neurotoxic effect have been seen in cancer patients receiving CAR-T cell therapy, but in this study, three patients experienced grade 1 CRS and the other two showed no signs of it; no patients had nervous-system effects. Three patients also had mild fevers and two had none. No infections occurred.

Obviously many questions remain about CAR-T cell therapy for SLE. Is it really a permanent cure or just a temporary stopgap? Will it be as safe as in this pilot trial when applied to larger and more diverse patient populations?

Cost could be another issue: approved CAR-T cell therapies have been priced at nearly $400,000, and that does not include the associated costs for patient preparation and follow-up. put the average total for a single cancer patient at about $700,000, which may be more than payers and patients are willing to stomach unless it's a genuine, one-and-done cure for lupus.

On the other side, this early success in SLE is likely to provoke interest in applying CAR-T cell therapy to other autoimmune conditions in which B cells play a prominent role, such as multiple sclerosis. Moreover, as noted, the technology can theoretically be adapted to targets other than B cells, opening the door to applications in a host of other diseases. Indeed, one Chinese company called Yake Biotechnology now has six studies of a CAR-T cell product for autoimmune and other non-cancer diseases (along with two dozen studies in hematologic malignancies).

  • author['full_name']

    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The study had no commercial funding.

Some authors reported relationships with numerous commercial entities unrelated to the study.

Primary Source

Nature Medicine

Mackensen A, et al "Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus" Nature Med 2022; DOI: 10.1038/s41591-022-02017-5.