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.
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, T-cells are isolated, transduced with a lentiviral vector containing the MAGE-A4c1032TCR, 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: 0.1 × 109 (±20%), 1 × 109 (range: 0.5 – 1.2 × 109), and 5 × 109 (range: 1.2 – 6 × 109), 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).
3 patients were treated with 0.1 × 109 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.
MAGE-A4 SPEAR T-cells at the 0.1 × 109 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.
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Editorial assistance was provided by Envision Pharma.
E. Van Winkle, K.D. Chagin, R.G. Amado: Employee: Adaptimmune. All other authors have declared no conflicts of interest.