Initial safety assessment of MAGE-A4 SPEAR T-cells

Abstract

Background: This ongoing study (NCT03132922) evaluates the safety and tolerability of genetically engineered autologous specific peptide enhanced affinity receptor (SPEAR) T-cells (MAGE-A4c1032T cells) directed towards a MAGE-A4 peptide expressed on tumors in the context of HLA-A*02. Method(s): This first-in-human T-cell dose-escalation study utilizes a modified 3+3 design to evaluate safety, including dose-limiting toxicities (DLT). Patients who are HLA-A*02 positive (excluding*02:05 and*02:07) and have inoperable or metastatic (advanced) NSCLC, urothelial cancer, melanoma, synovial sarcoma, MRCLS, squamous cell head and neck, ovarian, gastric or esophageal tumors with MAGE-A4 expression and meet all other entry criteria are eligible for treatment. Following apheresis, Tcells are isolated, transduced with a lentiviral vector containing the MAGEA4 c1032TCR, and expanded. Prior to transduced cell infusion, patients are given lymphodepleting chemotherapy (Flu 30 mg/m2/d and Cy 600 mg/m2/d, on days -7, -6 and - 5 in dose groups 1 and 2, and additional Flu 30 mg/m2/d on day -4 in dose group 3). Groups 1, 2 and 3 will consist of 3-6 patients, and transduced cell doses will be as follows: 0.1x109 (+/-20%), 1 x109 (range: 0.5 - 1.2 x109), and 5 x109 (range: 1.2 - 6x109), respectively. The DLT observation period is the first 30 days following the infusion of SPEAR T-cells for each patient in all groups. Following dose escalation, up to 30 patients will be enrolled at 5 x 109 (range: 1.2 x 109 -10 x 109). Result(s): 3 patients were treated with 0.1x109 MAGE-A4 SPEAR T-cells, and transduced cells are detectable in peripheral blood. AEs for the first 2 patients reported at grade (G) >=3 include anemia, hypoglycemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia. Serious AEs included G4 hyponatremia, G3 atrial fibrillation, G3 syncope (unrelated to T-cell therapy), G1 CRS and G2 encephalopathy syndrome (both related), and G2 generalized muscle weakness (possibly related). None of the events were considered DLTs by the Safety Review Committee. Conclusion(s): MAGE-A4 SPEAR T-cells at the 0.1x109 transduced cell dose appear to show no evidence of on-target or off-target toxicity. Preliminary data support continued investigation of the TCR, and this trial is ongoing. Updated safety data will be presented.