Enhancing the Efficacy of a TCR T Cell Therapy, scRNA Seq Revealing Insights

Afamitresgene autoleucel or Afami-cel is an autologous TCR T cell therapy targeting the MAGE-A4 cancer or testis pHLA antigen. The treatment, developed by AdaptImmune, completed its Phase II trial named SPEARHEAD-1 for patients with synovial sarcoma and saw a 39% overall response rate and a 12 month duration of response. As a result, Afami-cel was granted US FDA accelerated approval in August 2024, being the first new treatment option for the disease in over a decade. 

AdaptImmune’s next generation TCR T cell therapy is named Uzatresgene autoleucel, or Uza-cel. The treatment uses the same MAGE-A4-targeting T cell receptor with the addition of a CD8α coreceptor. In an effort to broaden efficacy across cancer indications, adding the coreceptor should give the CD4+ and CD8+ helper T cells the ability to kill tumour cells while engaging the broader immune response. 

In its Phase I trial, Uza-cell has managed significant responses across a range of tumour types including head and neck, ovarian, and urothelial cancers. The trial has seen an overall response rate of 35% and a five month median duration of response. The response was significantly higher in patients with platinum resistant ovarian cancer at 40%, which kicked off a Phase II trial named SURPASS-3, testing Uza-cell in this indication. 

Uza-cel is manufactured using a novel process compared to Afami-cel. T cells are collected via apheresis before they isolated and edited to include the engineered TCR through lentiviral vector transduction. Uza-cel’s process differs to Afami-cel in the expansion stage: where the latter used a Xuri rocking platform bioreactor, Uza-cell uses a G-Rex platform and additionally included an AKT inhibitor. The goal of adding the inhibitor is to decouple T cell differentiation from the activation stimulation, hopefully resulting in a less differentiated phenotype with greater functional potential. 

Single-cell RNA sequencing revealed distinct gene expression profiles between Uza-cel and Afami-cel. Uza-cel contained a novel subset of cells not seen in Afami-cel, which may have contributed to its effectiveness. The inclusion of an AKT inhibitor during manufacturing increased the proportion of cells in this Uza-cel specific subset. 

Patients who received a higher dose of Uza-cel transduced CD4+, CD8+ cells, particularly those in cluster 6, achieved better recovery rates. This suggests the importance of the less differentiated T cell phenotype in therapeutic outcomes. The dose of cells received with this phenotype correlates with a greater peak recovery of their transduced cells post-infusion.