Introduction: Synovial sarcoma (SyS) and myxoid round-cell liposarcoma (MRCL) are rare, aggressive soft tissue sarcomas with poor outcomes at the advanced and metastatic stage. Novel therapeutic strategies are urgently needed. Afamitresgene autoleucel (afami-cel) is the first Food and Drug Administration (FDA)-approved, affinity-enhanced T-cell receptor (TCR) therapy targeting the cancer-testis antigen MAGE-A4 in HLA-A*02-positive patients.
Areas covered: This review summarizes clinical evidence from one early-phase study and the pivotal phase 2 SPEARHEAD-1 trial. Afami-cel achieved objective response rates of 39% in SyS and 25% in MRCL, with durable responses exceeding 11 months in SyS. The safety profile is manageable, with hematological toxicities from lymphodepletion and predominantly low-grade cytokine release syndrome; no treatment-related deaths occurred in SPEARHEAD-1.
Expert opinion: Afami-cel represents a milestone in sarcoma therapy, establishing proof of concept for engineered TCR T-cell therapies in solid tumors. However, challenges remain regarding HLA restriction, tumor microenvironment resistance, manufacturing delays and cost. Future efforts should focus on broadening applicability, optimizing combinations, and ensuring equitable access.
Keywords: Afamitresgene autoleucel; MAGE-A4; SPEARHEAD-1 trial; TCR T-cells; cancer testis antigen; myxoid round cell liposarcoma; synovial sarcoma.