Afami-Cel: A Promising Living Drug Treatment for Synovial Sarcoma

The Lancet published research showing that afamitresgene autoleucel (afami-cel), a genetically engineered T-cell therapy, produced meaningful and durable responses in heavily pretreated patients with metastatic or surgically unresectable synovial sarcoma.

Based on data from the SPEARHEAD-1 trial, these findings indicate that the United States Food and Drug Administration (FDA) has granted priority review to the biologics license application for afami-cel. If approved, it would be the first new treatment option for synovial sarcoma in more than 10 years.

The phase 2 trial discussed in this article enrolled and treated 52 patients with metastatic or surgically unresectable synovial sarcoma (44 patients) or myxoid round cell liposarcoma (8 patients). Their median age was 41, they had an eligible HLA-A*02 allele and MAGE-A4 expression, and they had received a median of 3 previous lines of therapy.

Following lymphodepletion, 20 patients received afami-cel treatment. All patients received a single dose of afami-cel. The median dose was 8.7 × 10⁹ transduced T cells, with a median transduction efficiency of 61.5%.

Results

• The overall response rate (ORR) was 37%, with all responses being partial. ORR was 39% in patients with synovial sarcoma and 25% in patients with myxoid round cell liposarcoma.
• The median time to response was 4.9 weeks. Median response duration was 11.6 months in patients with synovial sarcoma and 4.2 months in those with myxoid round cell liposarcoma.
• At a median follow-up of 32.6 months, median progression-free survival was 3.7 months for all patients, 3.8 months for patients with synovial sarcoma, and 2.4 months for those with myxoid round cell liposarcoma.
• Median overall survival was 15.4 months across the entire cohort. Among patients with synovial sarcoma, it was 16.9 months; it was not reached in responders and was 10.9 months in nonresponders.
• All patients experienced treatment-related adverse events (TRAEs). The most common grade 3 or higher TRAEs were cytopenias, particularly lymphopenia (96%), neutropenia (85%), and leukopenia (81%).
• Grade 1-2 cytokine release syndrome (CRS) occurred in 69% of patients. One patient (2%) experienced grade 3 CRS, and there were no grade 4 or 5 CRS cases. There were no treatment-related deaths.

In conclusion, the findings suggest that a single treatment with afami-cel may extend life while allowing responding patients to stop chemotherapy. Publication of these data further confirms afami-cel's potential to address the unmet needs of people facing these common diseases.

The target decision date for the afami-cel FDA approval application was set as 4 August 2024.

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How Does Afami-cel Work?

Afami-cel treatment uses a virus (a lentiviral vector) to add a specialized structure (TCR) to the patient's T cells. This structure can bind very strongly to a specific region of the cancer protein MAGE-A4 . This binding is supported by the HLA-A*02 molecule, triggering T cells to attack cancer cells carrying the MAGE-A4 protein. After afami-cel treatment, T cells recognize, attack, and destroy cancer cells while also releasing important defense molecules called cytokines. This process is particularly effective in cancers carrying high levels of the MAGE-A4 protein.

As a T-cell therapy, afami-cel has provided important findings indicating effectiveness across multiple solid (tissue- or organ-origin) tumors carrying the MAGE-A4 antigen. MAGE-A4 is a protein expressed in various solid tumors, including melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and ovarian, bladder, and gastroesophageal cancers. Its expression in healthy tissues is limited. Afami-cel's mechanism targets proteins inside cells that can only be recognized through T-cell receptors (TCRs), so it is expected to cause fewer adverse effects in healthy cells than CAR-T-cell therapies. This indicates an important advantage of TCR therapies in treating solid tumors.

Engineered T-cell therapies such as afami-cel can be called "living drugs". This term generally refers to therapies using living cells genetically modified in a laboratory to treat disease. Such treatments are an innovative approach, particularly for diseases such as cancer, and are usually derived from the patient's own cells.

How Do Afami-cel and CAR T-Cell Therapies Differ?

The table below summarizes the key differences between CAR T-cell therapy and TCR therapy (for example, afami-cel):