Afamitresgene autoleucel: The First T-Cell Receptor Therapy on the Market

Introduction

Synovial sarcoma (SS) is a rare and aggressive disease that accounts for 5% to 10% of all soft tissue sarcomas. SS is diagnosed in fewer than 1000 people in the United States every year and most often occurs in young adults. SS can develop in the extremities or in the soft tissue of the abdomen or lung, and it is slightly more common in men than in women. Although SS is initially sensitive to chemotherapy, patients tend to have very poor outcomes once metastasis happens, with 5-year survival rates being approximately 10% and median overall survival (OS) being approximately 16.2 months.^1,2 Second-line regimens are not standard, but options include pazopanib (Votrient; Novartis Pharmaceuticals), eribulin, dacarbazine, vinorelbine, and gemcitabine. However, response rates with these agents are very poor, with none exceeding 10%.

On August 2, 2024, the FDA granted accelerated approval to afamitresgene autoleucel (afami-cel; Tecelra; Adaptimmune, LLC), a MAGE-A4–directed genetically modified autologous T-cell immunotherapy, to treat adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy; are HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P positive; and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices.³ It is the first and only FDA-approved T-cell receptor therapy on the market.

Mechanism of Action

The T-cell receptor (TCR) is a transmembrane receptor located on the surface of T cells that recognizes antigens bound to major histocompatibility complexes on target cells, thereby stimulating an immune response from activated T cells. MAGE-A4 is a cancer-testis antigen expressed in several solid tumor cell types, including SS. It is normally expressed only in germ cells of the testicles and placenta, making it an attractive target for SS.

MAGE-A4 participates in the regulation of cell growth, the cell cycle, and apoptosis through the expression of p53-related genes, thereby maintaining the replication function of DNA and playing a crucial role in the development and progression of various malignancies. Additionally, MAGE-A4 can be processed intracellularly into antigenic peptides, forming complexes with HLA molecules, making it an enticing target for TCR therapies.⁴

Afami-cel is an autologous CD4+ and CD8+ T-cell product transduced with a self-inactivating lentiviral vector to express an enhanced affinity MAGE-A4-specific TCR. This TCR is shown to respond potently toward MAGE-A4 peptides presented on multiple common HLA-A2 alleles, including HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P.⁵

Dosing and Administration

Afami-cel is given on day 1 after the completion of lymphodepletion with fludarabine 30 mg/m² intravenously once daily on days –7 through –4 and cyclophosphamide 600 mg/m² IV once daily on days –5 through –3 (Figure). The recommended dose is between 2.68×10⁹ and 10×10⁹ MAGE-A4 TCR-positive T cells administered as a single intravenous infusion. Premedication with acetaminophen and an H1-antagonist is recommended 30 to 60 minutes prior to the infusion. Systemic corticosteroids should be avoided, given their ability to induce T-cell apoptosis and interfere with the mechanism of afami-cel.^3,6

Clinical Data

Afami-cel was first evaluated in a multicenter, dose-escalation, phase 1 trial (NCT03132922) in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including 16 (42.1%) patients with SS. Afami-cel showed acceptable safety and durable efficacy, especially in patients with metastatic SS. The FDA approval was based on the subsequent international, open-label, phase 2 SPEARHEAD-1 trial (NCT04044768).⁶

The primary endpoint of SPEARHEAD-1 was overall response rate (ORR) evaluated in the main investigational cohort, with key secondary endpoints including progression-free survival (PFS), OS, and safety. Additional cohorts were a part of the trial to allow for continued access to afami-cel. Patients ages 16 to 75 years with metastatic or unresectable SS or mixed round cell liposarcoma with good performance status (ECOG performance status of 0 or 1) and adequate organ function were included if they were positive for HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P and had a MAGE-A4 P score of 30 or higher. P score was calculated as (percentage tumor staining at intensity ≥2) plus (percentage tumor staining at intensity ≥3), giving a range of 0 to 100, where a higher score indicates stronger expression.⁶

A total of 373 patients were prescreened for HLA and MAGE-A4 expression; 268 did not meet criteria. A total of 52 patients were treated with afami-cel; 44 had SS and 8 had myxoid round cell liposarcoma. Included patients were heavily pretreated with a median of 3 prior lines of treatment (IQR, 2-4).⁶

The ORR for those with SS was 39%, with all responses being partial responses. Most patients (52%) had stable disease, with only 9% having progressive disease. The median time to first response was 4.9 weeks (95% CI, 4.3-8.1), with the median duration of response being 11.6 months (95% CI, 4.4-18). The median PFS was 3.8 months (95% CI, 2.6-6.4) with median OS not yet reached at a follow-up of 27.8 months (95% CI, 15.4-not evaluable).⁶

Adverse Events

The most common grade 3 or higher adverse events (AEs) in patients who received afami-cel were cytopenias (TABLE⁶). Grade 3 or higher leukopenia was seen in 81% of patients; 96% experienced lymphopenia, and 85% experienced neutropenia. Anemia was seen in 31% of patients, and thrombocytopenia in 19%. These cytopenias have the potential to be prolonged; 19% of patients continued to have grade 3 or higher cytopenia 4 weeks after afami-cel treatment. However, only 1 patient was still experiencing this by week 12.⁶

Despite the high incidence of cytopenias, infection rates were low overall; rates of grade 3 or higher infections of any type did not exceed 4%. All patients received prophylaxis against Pneumocystis pneumonia and herpes simplex, as well as antifungal and antibacterial prophylaxis per institutional standards.⁶

Cytokine release syndrome (CRS) was common, with 71% of patients developing CRS of any grade, primarily grades 1 or 2 (52% and 20%, respectively). One patient developed grade 3 CRS. The median time of onset of CRS was 2 days (IQR, 2-3), with a median duration of 3 days (IQR, 2-5). Thirty-seven percent of patients received tocilizumab (Actemra; Genentech), and 2 were also treated with corticosteroids. All cases of CRS resolved. Immune effector cell-associated neurotoxicity (ICANS) was rare, with 1 patient experiencing grade 1 ICANS concomitantly with CRS. This resolved after 1 day.⁶

Place in Therapy

The National Comprehensive Cancer Network guidelines recommend afami-cel as a category 2A treatment option for patients receiving second-line or later therapies for advanced/metastatic soft tissue sarcoma. The patients must be HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P positive, and their tumor must express the MAGE-A4 antigen.⁷

Clinical Considerations

Identifying individuals who will most likely benefit from treatment is a requirement for precision medicine therapeutic products such as afami-cel. Based on the mechanism of action of TCR T-cell therapy, screenings for HLA genotype and tumor antigen expression are the 2 components of the biomarker-driven identification of eligible patients.

Because patients must have a specific HLA type for the therapy to work, most patients will not be eligible; this was seen in the SPEARHEAD-1 trial. Of the 373 patients who were screened, 268 did not meet criteria, making this therapy an option only for a very select patient population. HLA typing can be completed in-house at some centers, but the majority of centers in the community providing the initial screening will send this test out for completion. Ensuring that the community providers are aware of the correct test to order is imperative for timely patient identification.

MAGE-A4 testing can be confusing not only for clinicians, but payers as well. The clinical trial assay (CTA) is different than what is used commercially (the market-ready assay, or MRA). The definition of MAGE-A4 positivity in the SPEARHEAD-1 trial was greater than or equal to 30% of cells that were greater than or equal to 2+ intensity by CTA immunohistochemistry (IHC) staining, whereas positivity using the MRA was determined to be greater than or equal to 75% of cells that were greater than or equal to 2+ intensity by MRA IHC testing. This discrepancy has left many confused as to what truly constitutes MAGE-A4 positive for therapy eligibility.

The time from leukapheresis until afami-cel is manufactured, has completed sterility testing, is preserved, and is returned to the institute for the patient to receive must be considered when proceeding with treatment. There is a risk of disease progression and/or changes in clinical status that could result in the patient no longer being fit enough to receive afami-cel during the manufacturing process. In SPEARHEAD-1, the median time from leukapheresis until afami-cel was manufactured was 40 days (IQR, 35-50).Bridging therapy was allowed during this time, but the 16 patients who received bridging therapy had a lower response rate of 25% than those who did not, with a response rate of 46%.As with other cellular therapy products on the market, a wash-out period specific to the type of therapy was required.⁶

Another unique consideration is that the lentiviral vector has short spans of genetic material that are identical to HIV and may yield false-positive results for some commercial HIV nucleic acid tests.³ It is important that all members of the health care team and the patient are aware of the potential for false positivity.

Logistical Considerations

This is a specialized therapy that only authorized treatment centers can administer. Currently, there are only 27 eligible treatment centers across the United States, making access to care difficult for patients who qualify. Thirty-three states do not have a single center that is able to administer afami-cel, making patients and their caregivers travel potentially hundreds of miles from home to receive therapy. Centers that have the infrastructure to provide these therapies outpatient also require patients and their caregivers to find local lodging during the process, adding another level of complexity.

Another consideration to note is that, unlike other cellular therapy products, afami-cel is given on day 1³; most stem cell transplant and cellular therapy programs are accustomed to day 0 being used to denote the day of the cellular therapy product infusion. This is a key point that all team members need to be fully educated on when interpreting time to AE onset in the trial and building the treatment plan. This may also create a logistical challenge when documenting the day of infusion. Most institutions have their electronic medical record configured to count the days of therapy once day 0 is entered, which may not be compatible if it is omitted.

Conclusion

Afami-cel is a novel TCR therapy offering a new approach for treating this aggressive cancer. Other second-line therapies for SS have very low response rates, making afami-cel a more attractive option in comparison. Unfortunately, only a small subset of patients will qualify, given the HLA typing and MAGE-A4 expression restrictions. Although afami-cel offers a niche group of patients with SS another therapeutic option, most patients with SS will have to seek other, less-optimal therapies.

References

1. Palmerini E, Staals EL, Alberghini M, et al. Synovial sarcoma: retrospective analysis of 250 patients treated at a single institution. Cancer. 2009;115(13):2988-2998. doi:10.1002/cncr.24370

2. Blay JY, von Mehren M, Jones RL, et al. Synovial sarcoma: characteristics, challenges, and evolving therapeutic strategies. ESMO Open. 2023;8(5):101618. doi:10.1016/j.esmoop.2023.101618

3. Tecelra. Prescribing information. Adaptimmune, LLC; 2024. Accessed November 12, 2025. https://www.fda.gov/media/180565/download

4. Zhu W, Yi Q, Chen Z; et al. Exploring the role and mechanisms of MAGEA4 in tumorigenesis, regulation, and immunotherapy. Mol Med. 2025;4;31(1):43. doi:10.1186/s10020-025-01079-8

5. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023;29(1):104-114. doi:10.1038/s41591-022-02128-z.

6. D’Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. 2024;403(10435):1460-1471. doi:10.1016/S0140-6736(24)00319-2

7. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 5.2024. Accessed March 18, 2025. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf