More Success for CAR T-Cell Therapy in Rheumatic Disease

MILAN -- Prospects are improving that autologous chimeric antigen receptor (CAR) T-cell therapy will find a home in rheumatology clinics, in light of favorable results presented here.

You may remember that last September, researchers led by Georg Schett, MD, of Friedrich Alexander University Erlangen-Nuremberg in Germany, reported complete medication-free remission of systemic lupus erythematosus (SLE) lasting up to a year in five patients. At that time, it was suggested that the treatment -- which first gained traction in oncology -- could be applied more widely in rheumatology.

Now just such an application has been reported at the European Alliance of Associations for Rheumatology (EULAR) meeting. In a poster with Jule Taubmann, MD, as lead author, Schett's group described extraordinarily favorable outcomes in two patients with anti-synthetase syndrome (ASS) following CAR T-cell therapy.

As well, Schett provided an update on the SLE program, which now includes seven patients followed for up to 22 months.

As in oncology, the treatment involves extracting T cells from the patient 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 re-injected into the patient, where they hunt down and kill the target cells.

For ASS, lupus, and 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 with no further autoantigen targeting.

Both ASS and lupus -- not to mention many other autoimmune diseases -- are antibody-driven and thus promising applications for a therapy targeting B cells. ASS is a rare subtype of myositis, with one incidence estimate of about 0.5 per 100,000 population, in which autoantibodies target transfer RNA synthetase species. This results in a range of clinical manifestations, with arthritis and interstitial lung disease being particularly prominent.

The new study involved two ASS patients, one man and one woman, both in their early 40s. Both had received multiple drug regimens, including the anti-B cell agent rituximab (Rituxan) without gaining meaningful relief. CAR T-cell preparations were made for them and delivered in a single intravenous dose following a conditioning regimen with cyclophosphamide and fludarabine.

Both patients reported near-total elimination of their very severe symptoms within about 4 months of dosing. Both scored their disease burden at 10 on a 10-point scale prior to treatment. In the first month, one rated their symptoms at 6 and the other at 3; both scored themselves at 1 at month 4. Physician-assessed disease improvement according to published criteria was close to 100% at the 4-month follow-up.

Objective radiological measurements corroborated these results. MRI scans showed "complete resolution of signal changes and normalization of muscle signal," the researchers reported. PET-CT imaging indicated that muscle and joint fibroblast activity was substantially reduced. Also, creatinine kinase levels dropped from extremely high baseline values (4,000 to 6,000 units/L) to below 100 units/L after treatment.

Notably, both patients had been taken off all other medications prior to CAR T-cell therapy and they remained drug-free through follow-up.

In his update of the SLE program, Schett reported nothing substantially new beyond what the group published in September, other than the addition of two patients and the longer follow-up. But just that fact made his report remarkable, insofar as none of the patients had lost remission, including one now almost 2 years out from the treatment.

At last follow-up (4-22 months), all seven had SLE Disease Activity Index scores of 0 and were in clinical remission under Definition of Remission in SLE criteria. Four of the patients had experienced cytokine release syndrome, but it was graded as mild, and none showed any signs of neurotoxicity.