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Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Alexandra Gyurdieva1, Stefan Zajic1, Ya-Fang Chang1
1GlaxoSmithKline, Collegeville, PA, USA.
Abstract:
Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
Insights
Biomarkers predicting response to letetresgene autoleucel (lete-cel) for metastatic synovial sarcoma include higher pre-infusion IL-15 and specific T-cell counts. Post-treatment, increased IFNγ, IL-6, and cell expansion correlate with response.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Letetresgene autoleucel (lete-cel), a T-cell therapy targeting NY-ESO-1, shows promise for metastatic synovial sarcoma.
- Previous studies reported a 50% overall response rate, but predictive biomarkers for response and resistance require further definition.
Purpose of the Study:
- To identify biomarkers associated with response to lete-cel in synovial sarcoma patients.
- To explore associations with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression.
Main Methods:
- Post-hoc analysis of clinical trial data (NCT01343043) involving 45 synovial sarcoma patients.
- Evaluation of pre-infusion and post-infusion cytokine levels, cell counts, cell expansion, and tumor gene expression.
- Correlation of these factors with treatment response.
Main Results:
- Responders exhibited higher pre-infusion IL-15 levels and received more transduced effector memory CD8+ T-cells per kg.
- Post-infusion, responders showed increased IFNγ, IL-6, and peak cell expansion.
- Tumor analysis revealed lete-cel infiltration and decreased macrophage gene expression, indicating tumor microenvironment remodeling.
Conclusions:
- Identified potential predictive biomarkers (IL-15, T-cell dose) and pharmacodynamic markers (IFNγ, IL-6, cell expansion) for lete-cel response.
- Findings may inform LDR selection, cell dosing, and strategies to enhance anti-cancer efficacy.
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