CELL INTELLIGENCE · 肿瘤细胞治疗研究

The efficacy of immune checkpoint inhibitors is limited in refractory solid tumors. T-cell receptor gene-modified T (TCR-T)-cell therapy has attracted attention as a new immunotherapy for refractory cold tumors. We first investigated the preclinical efficacy and mode of action of TCR-T cells combined with the pullulan nanogel:long peptide antigen (LPA) vaccine in a mouse sarcoma model that is resistant to immune checkpoint inhibition. Without lymphodepletion, the pullulan nanogel:LPA vaccine markedly increased the number of TCR-T cells in the draining lymph node and tumor tissue. This change was associated with enhanced CXCR3 expression in TCR-T cells in the draining lymph node. In the phase 1 trial, autologous New York esophageal squamous cell carcinoma 1 (NY-ESO-1)-specific TCR-T cells were infused twice into HLA-matched patients with NY-ESO-1 + soft tissue sarcoma (STS). The pullulan nanogel:LPA vaccine contains an epitope recognized by TCR-T cells, and it was subcutaneously injected 1 day before and 7 days after the infusion of TCR-T cells. Lymphodepletion was not performed. Three patients with refractory synovial sarcoma (SS) were treated. Two out of the three patients developed cytokine release syndrome (CRS) with low-to-moderate cytokine level elevation. We found obvious tumor shrinkage lasting for more than 2 years by tumor imaging and long-term persistence of TCR-T cells in one patient. In conclusion, NY-ESO-1-specific TCR-T-cell therapy plus vaccination with the pullulan nanogel carrying an LPA containing the NY-ESO-1 epitope without lymphodepletion is feasible and can induce promising long-lasting therapeutic effects in refractory SS (Registration ID: JMA-IIA00346).