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

1Chimeric antigen receptor-modified (CAR) T cells targeting CD19 (CART19) have shown therapeutical activities in refractory/relapsed acute lymphocytic leukemia (ALL). Neurologic complications were reported in several trials; however, the etiological nature still remains a conundrum. In our recent CART19 clinical trial (ChiCTR-OCC-15007008), the evidence of blood-brain barrier (BBB)-penetrating CAR T cells as a culprit was revealed.

2An enrolled female patient of BCR/ABL p210(+) refractory/relapsed ALL with previous recurrence of central nervous system lymphoma (CNSL) was infused with autologous CART19 after conditioning chemotherapy with fludarabine and cyclophosphamide (detailed patient and methodological information was included in Fig. 1a and Additional file 1). CART19 preparation and infusion were described in Fig. 1b, c and Additional file 2. About 6 h after CART19 infusion, the patient developed sustained pyrexia with tremors (Fig. 2a). Three days later, the patient complained of headache, vomit, and recurrent right-sided facial and limb paresis with a homolateral blurred vision and defective visual field. Physical examination showed decreased myodynamia (grade 3), high blood pressure, and positive Babinski and Kernig signs. Papilloedema was observed by ophthalmoscope. Contrast-enhanced magnetic resonance imaging showed signs of intracranial edema (Fig. 2b). Serum cytokines including INF-γ, IL-6, and IL-10 elevated synchronously, supporting a grade 2 cytokine release syndrome (CRS) (Fig. 2c). The cerebral symptoms were not relieved by a bolus infusion of mannitol. Lumbar puncture on day 5 showed an over 400-mmH2O cerebrospinal pressure. The cerebrospinal fluid (CSF) contained 20 WBCs/μL and 4.0 g/μL protein (Fig. 2d). CD3+ T cells were predominant in CSF, with few CD19+ B cells (Fig. 2e) which excluded CNSL. qPCR analysis for CAR construct showed 3,032,265 copies/μg DNA in CSF and 988,747 copies/μg DNA in blood. Cytokine levels in CSF were extremely higher than those in the serum, with IFN-γ at 2977 versus 152 pg/ml and IL-6 at 8475 versus 46 pg/ml (Fig. 2c). Methyprednisone was administrated at 3 mg/kg/day since day 5, and the symptoms relieved gradually. By day 9, all cerebral symptoms and signs disappeared, and serum IFN-γ and IL-6 levels decreased to normal ranges. Then, methyprednisone was de-escalated and tapered on day 14. The patient achieved complete remission (CR) with minimal residual disease (MRD) negative 10 days after CART19 infusion.

3In the current study, the patient had experienced recurrent CNSL before CART19 infusion. Since CNS tissues lack CD19 expression, the CNS complications might less probably result from direct interactions between CD19+ cells and CART19. The predominance of CART19 in CSF and the huge discrepancies in inflammatory cytokine distributions strongly indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. Although no evidence of WBCs in CSF was observed before CART19 infusion, potent minimal residual CD19+ leukemia cells less than detection limits might enter CNS and dramatically trigger activation of CAR T cells. Notably, this patient complicated severe cerebral CRS rather than systemic compromisations, suggesting that systemic and cerebral CRS were independent processes.

4We have to acknowledge the comprehensive roles of CRS in CAR T cell therapy. Theoretically, cerebral CRS might facilitate elimination of CNSL and also cause severe CNS complications. Therefore, the timing and strategy to terminate CRS should be deliberately evaluated in clinical practice. Previous reports showed neurologic toxicities were not prevented by cytokine blockade via tocilizumab due to its incapability of crossing the BBB. Our experience of using glucocorticoid as a salvage option could be instructive for a quick control of the severe CRS.

5In all, we reported for the first time the development and control of cerebral CRS triggered by BBB-penetrating CAR T cells. This study provided insights into the etiology, diagnosis, and treatment of CRS after CAR T cell therapy.

6ALL, acute lymphocytic leukemia; BBB, blood-brain barrier; BM, bone marrow; CAR T cell, chimeric antigen receptor-modified T cell; CART19, CD19-directed CAR T cell; CNSL, central nervous system leukemia; CR, complete remission; CRS, cytokine release syndrome; CSF, cerebrospinal fluid; MRD, minimal residual disease; PB, peripheral blood; WBCs, white blood cells