For example, she contrasted the phenomenal results of a case series studies included in the systematic review with results from a much earlier study of SLE patients and rituximab, a B cell-depleting monoclonal antibody.2,4 Unlike the way rituximab is usually administered today, these patients received two doses of cyclophosphamide and oral corticosteroids with their rituximab treatment. At six to 88 months’ follow-up, 42% of patients were in full remission and 47% were in partial remission, and the majority had stopped immunosuppressive therapy.4
Although not as high as the rates reported for CAR T, these sorts of relatively high remission rates are not what most rheumatologists would associate with rituximab for SLE. Dr. Merrill noted that this study provides a closer (though imperfect) comparator to recent work in CAR T and SLE: CAR T protocols include chemotherapy such as cyclophosphamide and fludarabine, with some patients also receiving tocilizumab and potentially corticosteroids.
In essence, Dr. Merrill noted that one can’t fairly compare CAR T treatment to other earlier B cell-depleting options without also considering the potential impact of chemotherapy. It’s unclear if early chemotherapy would make a long-term difference, she said, but it’s worth considering.
For example, a study analyzed differences in molecular gene expression in SLE after CAR T with treatment after rituximab alone or treatment with cyclophosphamide alone. This revealed differences, such as changes in type 1 and type 2 interferon pathways.5
“What would happen if you did add chemotherapy to rituximab?” asked Dr. Merrill. “What would the differences be then? This is the kind of work we need to see done before we really understand what we’re looking at with CAR T.”
Thus, much work lies ahead to move the field forward. Part of that will mean innovations to help make these therapies potentially safer, cheaper, faster and more accessible. These might include innovations such as CAR using natural killer cells, other targets such as BCMA, in vivo CAR T, bispecific cell engagers or other approaches. But it will also necessitate employing basic principles of controlled trials and placebo groups and doing the deeper work to truly understand these processes at a molecular level.
“When something new comes along, there’s a tendency to try to explain it before we understand it,” said Dr. Merrill. “It’s exciting, but we have a lot of science to do.”
Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.
