CAR T Gets the Spotlight. Are We Missing the B Cells That Matter? Save

CAR T is having its moment in rheumatology. But William Robinson’s presentation at ACR Convergence 2026 raised a question I find even more compelling: are we failing to eliminate the right B cells with therapies we already have?

Using EBV-seq, Robinson’s group identified rare Epstein–Barr virus (EBV)-positive B cells in systemic lupus erythematosus (SLE) and multiple sclerosis. These were not passive viral reservoirs. Predominantly CD27+CD21low memory B cells, they displayed an activated antigen-presenting cell (APC) phenotype. Viral EBNA2 promoted ZEB2 and T-bet expression, driving proinflammatory antigen presentation. In SLE, these cells also encoded antinuclear antibodies and stimulated autoreactive T- and B-cell responses in coculture.

The therapeutic contrast was striking. In laboratory killing assays, EBV-positive B cells were relatively resistant to rituximab, obinutuzumab, ocrelizumab, and CD19-directed inebilizumab compared with EBV-negative cells. Enhanced survival and antiapoptotic programs offered a plausible, though unproven, explanation. Conversely, CD19 CAR T was associated with reduced EBV-positive B-cell frequencies and a less autoreactive reconstituted repertoire. Among SLE-derived antibodies tested, HEp-2 reactivity was seen in 12 of 14 before CAR T, but only 1 of 10 afterward in patients maintaining drug-free remission.

Interestingly, EBV itself was not eradicated. It appeared in reconstituting B cells, but with a less autoreactive repertoire. Perhaps the goal is not eliminating the virus, but resetting the cells it has reprogrammed.

That is exciting, but I am not convinced CAR T should be our only ambition. Cytokine-release syndrome, neurotoxicity, infection, lymphodepleting chemotherapy, cost, and access remain meaningful concerns. Extraordinary results do not make those tradeoffs disappear.

I would love to see an obinutuzumab-like next-generation depleter engineered to recognize features of these pathogenic, APC-like B cells—or overcome their survival machinery—without requiring cellular therapy. Not simply deeper depletion, but smarter depletion. Achieving specificity, however, remains a major challenge.

These early findings come from small cohorts and experimental assays, not a randomized head-to-head trial. They do not prove that selective removal of EBV-positive B cells causes remission. Still, rather than asking only how to scale CAR T, shouldn’t we also ask what it eliminates—and whether a safer, more accessible therapy could accomplish the same reset?

References 

Younis et al. Science Translational Medicine. 2025. PMID: 41223250. 

Courtney et al. bioRxiv. 2026. DOI: 10.64898/2026.10.24.761515. (Primary citation)