CAR-Modified T Cells Have Antitumor Activity in Refractory Adult 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.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.