Engineered Anti-MAGE-A T-Cells Show Early Promise

Genetically engineered T-cells targeting a common tumor antigen appeared safe and demonstrated some evidence of antitumor activity in a first-in-human clinical evaluation.

Marcus Butler, MD

Genetically engineered T-cells targeting a common tumor antigen appeared safe and demonstrated some evidence of antitumor activity in a first-in-human clinical evaluation.

The first 6 patients treated with either of 2 doses of engineered T-cells targeting melanoma-associated antigen-A4 (MAGE-A4) had a variety of adverse events (AEs), but treatment-related grade ≥3 AEs occurred in a minority of the patients. Four of the 6 heavily pretreated patients had stable disease as best response, including 1 who had ongoing stable disease at 6 weeks, as reported in a poster presentation at the European Society for Medical Oncology Annual Congress in Munich, Germany.

“MAGE-A4 SPEAR (specific peptide enhanced affinity receptor) T-cells at the 0.1 x 109 and 1.0 x 109 transduced doses appear to show no evidence of alloreactivity or off-target toxicity,” Marcus Butler, MD, of Princess Margaret Cancer Center in Toronto, and colleagues concluded. “The most frequent adverse events and treatment-related adverse events are consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies.”

“Transduced T-cells are detectable in the peripheral blood and expand transiently at lower doses and exhibit greater peak and duration of persistence at a higher T-cell dose…Preliminary data support continued investigation of MAGE-A4 SPEAR T-cells in the study populations.”

A broad variety of solid tumors express MAGE-A4. Genetically engineered SPEAR T-cells directed against a MAGE-A4 peptide (MAGE-A4c1032 T-cells) expressed on tumors, in the context of human leukocyte antigen (HLA)-A*02 have been developed for evaluation in patients with various advanced solid tumors. Butler and colleagues reported findings from the ongoing initial dose-finding clinical evaluation of the engineered T-cells.

Patients eligible for the trial are HLA-A*02+ (excluding *02:05 and *02:07 or null as sole *02 allele). Qualifying cancers consist of MAGE-A4+ inoperable or metastatic non—small cell lung cancer, urothelial cancer, melanoma, synovial sarcoma, myxoid/round cell liposarcoma, squamous cell head and neck cancer, ovarian cancer, gastric cancer, or esophageal cancer.

Groups of 3 to 6 patients receive MAGE-A4c1032 T-cells at doses of 0.1 to 5 x 109 cells, following fludarabine-cyclophosphamide condition. The trial will proceed to an expansion phase to a total of 30 patients, with the remaining patients treated at the highest tolerated dose.

The first 6 patients treated with the engineered T-cells all had stage IIIc-IVa ovarian cancer. Their ages ranged from 39 to 78, and they had received multiple prior therapies.

All 6 patients had grade ≥3 lymphopenia and neutropenia, but only 1 case each was considered treatment-related. Five patients had decreased appetite, fatigue, and nausea, none of which reached grade ≥3 severity. Four patients each developed anemia (all grade ≥3), dyspnea (no grade ≥3), and leukopenia (all grade ≥3). Febrile neutropenia occurred in 3 patients (all grade ≥3), and 3 patients developed thrombocytopenia (grade ≥3 in 2 of 3 cases). No patient had a dose-limiting toxicity as determined by investigator and Safety Review Committee assessment.

Four patients had a total of 8 serious AEs, consisting of 1 case each of pancytopenia, atrial fibrillation, cytokine release syndrome (treatment-related), hyponatremia, muscular weakness (treatment-related), encephalopathy (treatment-related) syncope, and pleural effusion.

Laboratory analyses of patients treated at the first 2 dose levels showed persistence of the engineered T-cells in peripheral blood for as long as 100 days. Follow-up continued in some cases.

Enrollment continues at the third dose level of the engineered T-cells (5 x 109 cell dose).

Hong D, Butler M, Johnson M, et al. Initial Safety Assessment of MAGE-A4 Specific Peptide Enhanced Affinity Receptor (SPEAR) T-Cells. Presented at the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 1156P.

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