Anti-CD19 CAR T cells for refractory myasthenia gravis

Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19(-)CD38(hi)CD138(+) subset was morphologically distinct, differentially expressed PC-associated genes, and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for more than 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19(-)CD38(hi)CD138(+) PCs in the BM. Finally, we found that CD19(-)CD38(hi)CD138(+) PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and probably represents the B cell response's "historical record" of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.

Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are effective treatment for B-cell lymphoma but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-humans clinical trial of T cells expressing the novel anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of CAR T-cell blood levels, anti-lymphoma activity, second infusions, and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remissions. Hu19-CD828Z T cells had similar clinical anti-lymphoma activity as T cells expressing FMC63–28Z, an anti-CD19 CAR tested previously by our group that contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells versus 50% of patients who received FMC63–28Z T cells (P=0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63–28Z. Lower levels of cytokines were detected in blood of patients receiving Hu19-CD828Z T cells versus FMC63–28Z T cells, which could explain the lower level of neurologic toxicity with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.