C-Reactive Protein May Indicate Risk of CAR T cell-Induced Toxicity

The adoptive transfer of tumor-specific, chimeric antigen receptor (CAR) T cells has emerged as a potentially effective therapy for hematologic malignancies. Davila and colleagues report complete findings from the largest phase I trial of CAR T-cell therapy to date in which 16 adult patients with relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) were treated with autologous T cells engineered to target the B-cell–specific antigen CD19. Consistent with previous results, CAR T-cell therapy was highly effective, producing complete responses in 88% of patients and molecular complete remissions in 75% of patients. However, a known but poorly characterized consequence of CAR T-cell therapy is a substantial increase in inflammatory cytokines with subsequent fever, hypotension, hypoxia, and neurologic changes, a severe but reversible phenomenon called cytokine release syndrome (CRS). The authors found that blockade of the interleukin-6 (IL-6) receptor with the monoclonal antibody tocilizumab ameliorated severe CRS symptoms without affecting expansion of CAR T cells, whereas steroid therapy reversed CRS symptoms but ablated CAR T cells. The authors also retrospectively analyzed patient serum samples and observed that only patients with high serum levels of C-reactive protein (CRP) showed signs of severe CRS, suggesting that CRP levels may be a surrogate for cytokine elevation that can potentially be used to predict which patients are at high risk for CRS. Of note, all patients in CAR T-cell–induced complete remission who were eligible for and received an allogeneic hematopoietic stem cell transplant have not relapsed, providing evidence that CAR T-cell therapy can be an effective bridge to curative therapy. In addition to providing strong support for further evaluation of CD19-targeted CAR T cells in B-ALL in a multicenter phase II study, these findings provide a framework for the management of patients treated with adoptive T-cell therapy.

Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra5.

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