Adaptimmune is a therapeutics company specializing in CAR-T cell therapy for solid tumors and allogeneic cell therapies. Their leading product, afami-cel, comes onto market late 2024, for the treatment of synovial sarcoma. They are currently scaling up clinical operations to serve afami-cel following the approval of their Biologics License Application (BLA) by the FDA in early 2024. Adaptimmune is poised to build a product profile around sarcoma, estimating they will capture $400M annually in revenue in the treatment of synovial sarcoma (afami-cel, lete-cel) and myxoid/round cell liposarcoma (MRCLS) (lete-cel).
Overall, Adaptimmune is well positioned to be one of the first to market with a CAR-T cell therapy for solid tumors. However, the return of lete-cel and ADP-600 to the company from GSK, as well as the axing of the allogeneic partnership with Genentech may signal risk for the upcoming pipeline, or possibly just a shrinkage of programs from the pharmaceutical giants.
Synovial Sarcoma is a rare soft tissue tumor, most common in individuals under 30, with a 5-year survival rate between 36%-76% (Adaptimmune reports this number to be 20%). It is characterized by its location near joints, its potential to spread to the lungs, and its high potential for metastasis. The disease often results from a chromosomal mutation, specifically the fusion of SYT on chromosome 18 to either SSX1 or SSX2 on the X chromosome. Current treatments include surgical removal of the tumor, with or without chemo or radiation therapy, and the kinase inhibitor pazopanib.
Adaptimmune estimates that there are 13,000 new soft tissue sarcoma cases in the US per year, with 5-10% (650 - 1300 cases) of these being synovial sarcoma.
CURRENT TREATMENTS (link)
Afami-cel, also known as afamitresgene autoleucel, is a CAR-T cell therapy that targets the MAGE family of cancer testis antigens, primarily focusing on the MAGE-A4 antigen.
The therapy underwent a Phase 1 clinical trial from 2017 to 2022, which included patients with synovial sarcoma, ovarian cancer, and head and neck cancer. The outcomes of this trial were primarily focused on evaluating adverse events, dose limiting toxicities, the longevity of modified T cells, and the presence of replication-competent retrovirus. Secondary outcomes included assessing complete or partial response, time and duration of response, duration of stable disease and progression-free survival, and long-term adverse events such as new malignancies.
From this trial, it was found that out of 68 participants, only 20 made it to long term follow up, and 38 were treated with afami-cel. All these patients experienced Grade≥3 hematologic toxicity, which cannot be attributed to lymphodepletion that occurs prior to CAR-T application. Additionally, 55% of patients experienced cytokine release syndrome, a common side effect of CAR-T therapy.
The overall response rate was 24%, with no complete responses recorded. However, for patients with Synovial Sarcoma, the response rate was higher at 44%, and only 9% for other types of cancers. These results perhaps influenced the decision to focus the Phase 2 trials on Synovial Sarcoma and Myxoid/Round Cell Liposarcoma.
The Phase 2 trial, known as SPEARHEAD-1, started in 2019 and is still ongoing (awaiting long-term results). This trial was open-label, meaning both patients and doctors were aware of the treatment being administered. The trial aimed to study the safety and efficacy of afami-cel in HLA-A*02 eligible and MAGE-A4 positive subjects with advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma.
The primary outcome was the efficacy of the treatment defined by complete or partial responses. The secondary outcomes included safety measurements related to adverse effects, replication-competent retrovirus in the T cells, and T-cell clonality and insertional oncogenesis by lentivirus. The results for Cohort 1, which consisted of 52 patients, appeared to be similar to the Phase 1 trial, with a 37% partial response for Synovial Sarcoma, and 25% for Myxoid round cell liposarcoma.