In a phase II SPEARHEAD-1 study involving patients with previously treated, HLA-A*02-positive, and MAGE-A4-positive synovial sarcoma and myxoid round cell liposarcoma, treatment with lymphodepletion chemotherapy and afamitresgene autoleucel resulted in an overall response rate of 37% and durable responses with median of 11.6 months.
By meeting its primary endpoint, this study provides a proof of principle for the use of T-cell receptor T-cell therapy against solid tumours according to Dr. Sandra P D’Angelo of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues who published the findings on 27 March 2024 in The Lancet.
Synovial sarcoma and myxoid round cell liposarcoma are rare mesenchymal malignancies that comprise 5-10% of all soft tissue sarcomas. Despite initial sensitivity to chemotherapy, these aggressive tumours tend to have very poor outcomes once they metastasise. Although synovial sarcoma and myxoid round cell liposarcoma are distinct diseases, they share clinical and biological features. They highly express cancer testis antigens, including MAGE-A4 and NY-ESO-1.
Both synovial sarcoma and myxoid round cell liposarcoma are characterised by unique pathognomonic chromosomal translocations. Their associated tumour immune microenvironments have few T-cells and antigen-presenting cells, low PD-L1 expression, and low frequency of non-synonymous somatic mutations, explaining the limited efficacy of checkpoint inhibitors in this setting.
Afamitresgene autoleucel is an autologous CD4+ and CD8+ T-cell product transduced with a self-inactivating lentiviral vector to express an affinity-enhanced MAGE-A4-specific T-cell receptor. Preliminary efficacy of afamitresgene autoleucel was shown in a phase I study. The aim of SPEARHEAD-1 study was to evaluate the efficacy of afamitresgene autoleucel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.
SPEARHEAD-1 was an open-label, non-randomised, phase II study done across 23 sites in Canada, the USA, and Europe. The study included three cohorts, of which the main investigational cohort (cohort 1) is reported in the article published in The Lancet. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma confirmed by cytogenetics expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afamitresgene autoleucel (transduced dose range 1.0×10⁹–10.0×10⁹ T-cells) after lymphodepletion.
The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using RECIST v1.1 in the modified intention-to-treat population defined as all patients who received afamitresgene autoleucel. Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. Recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3.
Between 17 December 2019 and 27 July 2021, 44 patients with cytogenetically confirmed synovial sarcoma and 8 patients with myxoid round cell liposarcoma were enrolled and received afamitresgene autoleucel in cohort 1. Patients were heavily pretreated with median three (IQR two to four) previous lines of systemic therapy. Median follow-up time was 32.6 months (IQR 29.4–36.1).
Overall response rate was 37% (95% confidence interval [CI] 24–51) overall, 39% (95% CI 24–55) for patients with synovial sarcoma, and 25% (95% CI 3–65) for patients with myxoid round cell liposarcoma. Median time to initial confirmed response was 4.9 weeks (95% CI 4.3–8.1) in patients with a response. Median duration of response was 11.6 months (95% CI 4.4–18.0) in patients with synovial sarcoma and 4.2 months (95% CI 2.9–5.5) in patients with myxoid round cell liposarcoma. Responses were observed across key subgroup covariates. Median progression-free survival was 3.7 months (95% CI 2.8–5.6) overall, 3.8 months (95% CI 2.8–6.4) in patients with synovial sarcoma, and 2.4 months (95% CI 0.9–7.4) in patients with myxoid round cell liposarcoma.
Cytokine release syndrome occurred in 37 of 52 of patients (71%) with one grade 3 event. Cytopenias were the most common grade 3 or worse adverse events with lymphopenia occurring in 96%, neutropenia in 85%, and leukopenia in 81% of patients. No treatment-related deaths occurred.
The authors commented that this study is limited by its single-arm, non-randomised design, which does not permit the conclusion that afamitresgene autoleucel is superior to systemic agents for refractory synovial sarcoma and myxoid round cell liposarcoma. A randomised study, however, would be difficult to conduct as no globally consistent second-line therapy exists for these patients, so selecting a comparator would be difficult, and HLA*A-02 typing and MAGE-A4 expression requirements would entail selection of subsets of these two very rare cancers, for which the estimated incidence is 1.55 per million people per year for myxoid round cell liposarcoma and 1.67 per million people per year for synovial sarcoma.
Solid tumours can have an immuno-suppressive microenvironment that makes effective treatment with cell therapy more challenging than for haematological malignancies. Additionally, few solid tumours express the tumour-specific surface antigens targeted by CAR T cells, whereas engineered T-cell receptor T-cell therapies such as afamitresgene autoleucel target intracellular antigens presented by HLA. This study shows the ability to effectively target solid tumour cancer antigens with T-cell receptor therapy and highlights MAGE-A4 as a new immunotherapy target for treatment of synovial sarcoma.
In an accompanied comment, Dr. Patrick Schlegel of the School of Medical Sciences, Faculty of Medicine and Health, University of Sydney and Department of Pediatric Hematology and Oncology, Westmead Children’s Hospital in Sydney, NSW, Australia wrote that the study authors provide valuable insights into the clinical dimensions of transgenic T-cell receptor immunotherapy, shedding light on patient-specific challenges and therapeutic intricacies that emerge during the rigorous stratification process.
The favourable median overall survival was observed with 15.4 months (95% CI 10.9–28.7) and an overall survival probability of 60% (95% CI 46−73) at 1 year after afamitresgene autoleucel infusion. The clinical response was clearly correlated with an improved survival probability and associated with the expression level of MAGE-A4, as well as the expansion and the persistence of the transgenic T-cell receptor-positive T-cells. The results of SPEARHEAD-1 show how patients with pressing medical needs reap the benefits of the collective endeavours of scientists working in the field of T-cell receptor-based immunotherapy.
This study was funded by Adaptimmune.
References
- 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. The Lancet; Published Online 27 March 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00319-2
- Schlegel P. T cells for advanced synovial sarcoma or myxoid round cell liposarcoma. The Lancet; Published Online 27 March 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00411-2