Project description:T cells targeting epitopes in infectious diseases or cancer play a central role in spontaneous and therapy-induced immune responses. T-cell epitope recognition is mediated by the binding of the T-Cell Receptor (TCR) and TCRs recognizing clinically relevant epitopes are promising for T-cell based therapies. Starting from one of the few known TCRs targeting the cancer-testis antigen NY-ESO-1 (157–165) epitope, we built large phage display libraries of TCRs with randomized Complementary Determining Region 3 of the β chain. The TCR libraries were panned against the NY-ESO-1 epitope, which enabled us to collect thousands of epitope-specific TCR sequences. We then trained a machine learning TCR-epitope interaction predictor with this data and could identify several epitope-specific TCRs directly from TCR repertoires. Cellular binding and functional assays revealed that the predicted TCRs displayed activity towards the NY-ESO-1 epitope and no detectable cross-reactivity with self-peptides. Overall, our work demonstrates how display technologies combined with machine learning models of TCR-epitope recognition can effectively leverage large TCR repertoires for TCR discovery.
Project description: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. Biomarkers predictive of response and resistance remain to be better defined. In 45 synovial sarcoma patients, we analyzed the association of response to lete-cel (NCT01343043) with tumor gene expression. Analysis of tumor samples post-treatment illustrated lete-cel infiltration and decreased expression of macrophage genes, suggesting remodeling of the tumor microenvironment.
Project description: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. Biomarkers predictive of response and resistance remain to be better defined. In 45 synovial sarcoma patients, we analyzed the association of response to lete-cel (NCT01343043) with tumor gene expression. Analysis of tumor samples post-treatment illustrated lete-cel infiltration and decreased expression of macrophage genes, suggesting remodeling of the tumor microenvironment.
Project description:In this work, we compared the expression profiles of Anti-NY-ESO1- transduced T-cells with Anti-NY-ESO1- transduced T-cells co-cultured with SK-Mel-37.
Project description:This phase I trial studies the side effects and best schedule of vaccine therapy with or without sirolimus in treating patients with cancer-testis antigen (NY-ESO-1) expressing solid tumors. Biological therapies, such as sirolimus, may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from a person’s white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells that express NY-ESO-1. Infusing the vaccine directly into a lymph node may cause a stronger immune response and kill more tumor cells. It is not yet known whether vaccine therapy works better when given with or without sirolimus in treating solid tumors.