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Spatiotemporal T-cell tracking for personalized T-cell receptor T-cell therapy designs in childhood cancer
I Sentís1, J L Melero2, A Cebria-Xart3
1Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Spain.
Background:
Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers.
Patients And Methods:
We present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized T-cell receptor T-cell (TCR-T) therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T-cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood.
Results:
Tracking T-cell dynamics longitudinally from the tumor to cells in circulation over a time course of 12 months revealed a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T-cell dynamics in the blood post-ICI to predict tumor reactivity.
Conclusions:
These findings strongly support spatiotemporal tracking of T-cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.
Insights
Tracking T-cell dynamics after immune checkpoint inhibition (ICI) identified tumor-reactive T cells. These cells can predict therapy efficacy and serve as candidates for personalized T-cell receptor T-cell (TCR-T) therapies in low-mutation cancers.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint inhibition (ICI) has transformed cancer treatment, improving survival in many cancers.
- However, low response rates and limited biomarkers are observed in low-mutational burden cancers, including pediatric malignancies.
Purpose of the Study:
- To develop a framework for identifying and validating tumor-reactive T cells.
- To use these cells as biomarkers for ICI efficacy and as candidates for personalized T-cell receptor T-cell (TCR-T) therapy.
Main Methods:
- Deep single-cell T-cell receptor (TCR) repertoire sequencing of tumor microenvironment (TME) and peripheral blood in a pediatric malignant rhabdoid tumor patient.
- Longitudinal tracking of T-cell dynamics over 12 months.
- Functional validation of tumor reactivity using TCR-engineered autologous T cells.
Main Results:
- Identified durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes.
- Observed high frequencies of tumor-reactive TCR clonotypes in the TME.
- Confirmed that T-cell dynamics in peripheral blood post-ICI can predict tumor reactivity.
Conclusions:
- Spatiotemporal tracking of T-cell activity in response to ICI is crucial for informing therapy efficacy.
- This approach provides a source of tumor-reactive TCRs for personalized TCR-T designs.
