CD19-specific CAR T cells rapidly eradicate resistant B-ALL and provide a bridge to allo-HSCT.
Major finding: CD19-specific CAR T cells rapidly eradicate resistant B-ALL and provide a bridge to allo-HSCT.
Mechanism: The response to 19–28z CAR-modified T cells was evaluated in 5 patients with relapsed B-ALL.
Impact: 19–28z+ T cells may induce complete molecular remission in patients with relapsed B-ALL.
Relapsed adult B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease with an extremely poor prognosis. The standard of care is treatment with salvage chemotherapy followed by allogeneic hematopoietic stem cell transplant (allo-HSCT) if patients are clinically eligible, but long-term survival is dependent on achieving remission without minimal residual disease (MRD) after chemotherapy. Transfer of autologous T cells modified to express chimeric antigen receptors (CAR) specific for the B-cell antigen CD19 has shown antitumor activity in low-grade B-cell malignancies, but it is not known whether this strategy is also effective in refractory B-ALL. Brentjens and colleagues treated 5 adult patients with relapsed B-ALL who had received salvage chemotherapy but not allo-HSCT with autologous T cells expressing a second-generation CD19-targeted CD28/CD3ζ CAR (19–28z). Infusion of modified T cells resulted in rapid elimination of resistant tumor cells and MRD− complete remission in all 5 patients, independent of tumor burden prior to T-cell therapy. CAR T cells expanded in vivo and were well tolerated but triggered elevations in proinflammatory cytokines in patients with greater residual tumor burden prior to T-cell infusion, necessitating high-dose steroid treatments to reduce toxicity. Following 19–28z+ T-cell therapy, 4 patients received allo-HSCT, including 2 patients with refractory disease after chemotherapy who would have otherwise been ineligible, indicating that CAR-modified T cells provide a bridge to allo-HSCT and may induce durable antitumor responses. One patient experienced tumor relapse that was not associated with antigen loss or insensitivity to T-cell–mediated lysis but was possibly due to steroid-induced reduction in T-cell persistence, suggesting that repeated T-cell infusions may extend remission. Although allo-HSCT precluded long-term follow-up in most patients, these results show that 19–28z+ T cells have antitumor activity in patients with refractory B-ALL and support additional studies of this therapeutic strategy.
Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra38.
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