FDA Grants First Approval for Chimeric Antigen Receptor (CAR) T-Cell Therapy in Solid Tumors: Afamitresgene Autoleucel for Synovial Sarcoma and Myxoid Round Cell Liposarcoma
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on November 8th, 2024
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Synovial sarcoma and myxoid round cell liposarcoma are rare types of soft tissue sarcoma that typically respond to chemotherapy. However, once these cancers metastasize, the prognosis is grim, with a 5-year survival rate of only 8% to 14%. Despite their differences, both tumor types express high levels of MAGE-A4. Recently, a study sponsored by Adaptimmune explored the use of afamitresgene autoleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting MAGE-A4, to treat patients with synovial sarcoma and myxoid round cell liposarcoma.
The phase 2 clinical trial enrolled 44 patients with synovial sarcoma and 8 patients with myxoid round cell liposarcoma. Only those with HLA-A*02 antigen-presenting cells and tumors expressing MAGE-A4 were included. Of the participants, 79% had stage IV disease, and 35% had previously undergone more than four lines of systemic therapy, including anthracycline or ifosfamide. One week prior to treatment, patients underwent leukodepletion, starting with intravenous fludarabine at 30 mg/m² daily for four days, followed by cyclophosphamide at 600 mg/m² daily for three days. To prevent opportunistic infections due to leukocyte depletion, antibiotic prophylaxis was administered. Afamitresgene autoleucel was then delivered intravenously at a dose of 1 to 10 billion T cells. Tocilizumab was available to manage cytokine release syndrome if needed. After a median follow-up of 32.6 months, partial tumor reduction was observed in 39% of synovial sarcoma patients and 25% of those with myxoid round cell liposarcoma. Mild to moderate cytokine release syndrome occurred in 69% of participants, with only one severe case. However, several life-threatening cases of leukopenia, lymphopenia, neutropenia, and pyrexia were reported. This trial demonstrated the potential of CAR T-cell therapy in targeting solid tumors, leading to afamitresgene autoleucel's approval by the US FDA in August 2024. The author acknowledged that the single-arm design of the study was a limiting factor, but this approach was intentional due to the absence of an international consensus on second-line therapies for synovial sarcoma and myxoid round cell liposarcoma. Furthermore, the potential application of afamitresgene autoleucel could be expanded by targeting additional HLA alleles.
The phase 2 clinical trial enrolled 44 patients with synovial sarcoma and 8 patients with myxoid round cell liposarcoma. Only those with HLA-A*02 antigen-presenting cells and tumors expressing MAGE-A4 were included. Of the participants, 79% had stage IV disease, and 35% had previously undergone more than four lines of systemic therapy, including anthracycline or ifosfamide. One week prior to treatment, patients underwent leukodepletion, starting with intravenous fludarabine at 30 mg/m² daily for four days, followed by cyclophosphamide at 600 mg/m² daily for three days. To prevent opportunistic infections due to leukocyte depletion, antibiotic prophylaxis was administered. Afamitresgene autoleucel was then delivered intravenously at a dose of 1 to 10 billion T cells. Tocilizumab was available to manage cytokine release syndrome if needed. After a median follow-up of 32.6 months, partial tumor reduction was observed in 39% of synovial sarcoma patients and 25% of those with myxoid round cell liposarcoma. Mild to moderate cytokine release syndrome occurred in 69% of participants, with only one severe case. However, several life-threatening cases of leukopenia, lymphopenia, neutropenia, and pyrexia were reported. This trial demonstrated the potential of CAR T-cell therapy in targeting solid tumors, leading to afamitresgene autoleucel's approval by the US FDA in August 2024. The author acknowledged that the single-arm design of the study was a limiting factor, but this approach was intentional due to the absence of an international consensus on second-line therapies for synovial sarcoma and myxoid round cell liposarcoma. Furthermore, the potential application of afamitresgene autoleucel could be expanded by targeting additional HLA alleles.