Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy

Abstract

Chimeric antigen receptor-modified (CAR) T cells targeting CD19 (CART19) have shown therapeutical activities in CD19+ malignancies. However, the etiological nature of neurologic complications remains a conundrum. In our study, the evidence of blood-brain barrier (BBB)-penetrating CAR T cells as a culprit was revealed. A patient with acute lymphocytic leukemia developed sustained pyrexia with tremors about 6 h after CART19 infusion, followed by a grade 2 cytokine release syndrome (CRS) and neurological symptoms in the next 3 days. Contrast-enhanced magnetic resonance showed signs of intracranial edema. Lumbar puncture on day 5 showed an over 400-mmH2O cerebrospinal pressure. The cerebrospinal fluid (CSF) contained 20 WBCs/μL with predominant CD3+ T cells. qPCR analysis for CAR constructs showed 3,032,265 copies/μg DNA in CSF and 988,747 copies/μg DNA in blood. Cytokine levels including IFN-γ and IL-6 in CSF were extremely higher than those in the serum. Methyprednisone was administrated and the symptoms relieved gradually. The predominance of CART19 in CSF and the huge discrepancies in cytokine distributions indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. For the first time, we reported the development of cerebral CRS triggered by BBB-penetrating CAR T cells.Trial registration: ChiCTR-OCC-15007008.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0299-5) contains supplementary material, which is available to authorized users.

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…151,156,159,160,165 The second focuses on direct T-cell infiltration into the cerebral spinal fluid (CSF) and brain. 108,151,152,165,170 Compelling new data also implicate breakdown of the blood-brain barrier (BBB) in CRES, supported by both histopathologic evidence and by the measurement of systemic biomarkers for endothelial disruption during CRES. 142,168 A recent study by Gust et al has proposed a pathophysiologic model of the interplay between CAR-Ts, cytokines, the BBB, and CRES.…”

CAR-T Cells and Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

“…Donor-derived allogeneic anti-CD19-CAR-T cells can cause regression of B-cell malignancies resistant to standard donor lymphocyte infusions without causing GVHD [9]. It is therefore a safe and feasible approach for patients to receive donor-derived CAR-T cell therapy for relapse after allo-HSCT [71,72]. Thus, early infusion of CAR-T cells could be used for the prevention of relapse for high-risk cases or when molecular relapse is detected.…”

“…Allogeneic CAR-T cells are beneficial for patients with relapsed B-cell malignancies after allo-HSCT, and have low toxicities and complications [68][69][70][71][72][73]. Recently, coinfusion of haploidentical donor-derived CD19-CAR-T cells and mobilized peripheral blood stem cells following induction chemotherapy was performed in a 71-year-old female with relapsed and refractory ALL.…”

Chimeric Antigen Receptor Therapeutic Strategies: The Future of Glioblastoma Management

“…The activation of T-cells through CAR therapy may lead to cytokine release syndrome (CRS), which has been reported in a number of studies, and may range from a mild to a serious complication [10][11][12][13][14].…”