The FDA approval of afamitresgene autoleucel (afami-cel; Tecelra) in August 2024 for unresectable or metastatic synovial sarcoma has paved the way for engineered cell therapies in solid tumors, spotlighting melanoma-associated antigen 4 (MAGEA4) as a key therapeutic target. This approval marks the first of its kind for a solid tumor, spurring interest in MAGEA4-directed agents for a range of cancers. MAGEA4, typically found in immune-privileged sites, is re-expressed in several cancers, including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, ovarian cancer, urothelial cancer, melanoma, and gastroesophageal cancers.
Afami-Cel: Setting a New Standard
Afami-cel is an autologous T-cell therapy engineered to target a MAGEA4 peptide. Preclinical studies demonstrated its potent cytotoxic effects against HLA-A02/MAGEA4-expressing cancer cells. The FDA's accelerated approval was based on findings from cohort 1 of the phase 2 SPEARHEAD 1 trial (NCT04044768). This open-label, nonrandomized study included patients with HLA-A02–positive, MAGEA4-expressing metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma who had received at least one prior line of chemotherapy.
Patients received a single intravenous infusion of afami-cel after lymphodepletion. The primary endpoint was overall response rate (ORR) per RECIST 1.1, assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. At a median follow-up of 32.6 months, the ORR in synovial sarcoma patients (n=44) was 39% (95% CI, 24%-55%), while myxoid round cell liposarcoma patients (n=8) had an ORR of 25% (95% CI, 3%-65%). The median OS for synovial sarcoma was not reached (95% CI, 15.4-not estimable), and the median PFS was 3.8 months (95% CI, 2.8-6.4).
According to Brian A. Van Tine, MD, PhD, sarcoma program director and professor of medicine at Washington University in St Louis, durable responses have been observed in some patients treated with afami-cel. "If you can get a deep response, [it] can be incredibly durable, and this [is accompanied by a] high quality of life because there’s no more chemotherapy, no oral medications—there’s nothing other than getting surveillance scans," he stated.
Safety Profile of Afami-Cel
In the SPEARHEAD 1 trial, all patients experienced treatment-emergent adverse effects (TEAEs). The most common TEAEs included cytokine release syndrome (CRS; 71%), decreased white blood cell count (27%), pyrexia (23%), and decreased neutrophil count (23%). Grade 3 or worse cytopenia occurred in 19% of patients. Notably, there were no treatment-related deaths within the first 30 days following afami-cel infusion.
David S. Hong, MD, deputy chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, noted that CRS with cellular therapies in solid tumors tends to be less toxic than in lymphomas. "The vast majority of these patients had grade 1 or 2 [CRS], which is somewhat different than [the CRS from] chimeric antigen receptor T-cell therapies being developed in lymphoma," he said.
Expanding the MAGEA4-Targeted Approach
Beyond afami-cel, other MAGEA4-directed agents are under development. IMA401, a next-generation, half-life–extended TCR-based bispecific T-cell engager targeting MAGEA4 and MAGEA8, is being evaluated in a phase 1 study (NCT05359445) for recurrent or refractory solid tumors. Initial data presented at the 2024 European Society for Medical Oncology Congress showed an ORR of 21% in efficacy-evaluable patients (n=29) who were heavily pretreated. Patients with high MAGEA4/8 expression (n=17) achieved an ORR of 29% and a disease control rate of 53%. The toxicity profile was manageable, with low-grade CRS, transient lymphopenia, and neutropenia being the most common treatment-related adverse events.
MT-601, a novel multi-tumor-associated antigen-specific T-cell agent, is being investigated in the phase 1 APOLLO trial (NCT05798897) for relapsed/refractory lymphoma. MT-601 targets six tumor antigens, including MAGEA4. Preliminary findings presented at the Global Summit on Hematologic Malignancies in April 2024 highlighted a complete response in a patient with follicular non-Hodgkin lymphoma after 12 prior treatment failures, including CAR T-cell therapy. Another patient with DLBCL achieved a partial response with MT-601 at 8 weeks post-treatment.
According to Van Tine, the approval of afami-cel and the ongoing development of other MAGEA4-directed therapies represent a transformative shift in oncology practice. "There’s going to be this new academic-private practice partnership for managing these therapies, which is new for the solid tumor doctors... This is going to change how oncology is practiced, but for the patients in whom it works, it’s the most transformative thing I’ve seen in my career."
