Abstract
Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted.Trial Registration NumbersNCT 03423992
Highlights
Half of primary brain tumor are gliomas
The chimeric antigen receptor T cells (CAR T-cells) therapy has changed the paradigm of treatment for patients with hematologic malignancy [5]
There have been four clinical studies evaluating 31 glioblastoma patients who have received CAR T-cells immunotherapy targeted against IL13R2, EGFRvIII, and HER-2 respectively [6,7,8,9]
Summary
Half of primary brain tumor are gliomas. Most glioma will evolve into their most malignant form, glioblastoma [1]. Four months after the surgery, MRI revealed recurrence of the glioblastoma involving left frontal and corpus callosum, for which she was referred to our clinical trial On evaluating her tumor sample before enrollment, the immunohistochemistry (IHC) study demonstrated an EphA2-positive glioblastoma (Figure 2A). She received the CAR T-cells infusion on June 22, 2018 (profile of her CAR Tcells was described in Supplementary Table 1). IHC studies revealed an EphA2 positive glioblastoma (Figure 3A) He received the infusion on August 14, 2018 (CAR T-cells profile in Supplementary Table 1). He participated in our clinical trial because of tumor residue (Figure 4A) and was administrated CAR T-cells on August 28, 2018 (CAR T-cells profile in Supplementary Table 1) This patient developed a high fever on day 1 (7 hours after the infusion), which lasted for 6 days. This patient was reported as PD with an OS of 86 days
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