Exploitation of differential homeostatic proliferation of T-cell subsets following chemotherapy to enhance the efficacy of vaccine-mediated antitumor responses |
| |
Authors: | Sofia R Gameiro Jorge A Caballero Jack P Higgins David Apelian James W Hodge |
| |
Institution: | (1) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B13, Bethesda, MD 20892, USA;(2) GlobeImmune Inc., Louisville, CO, USA; |
| |
Abstract: | The 5-year survival rate for stage IB-III non-small-cell lung cancer (NSCLC) remains 15%. Surgical resection followed by adjuvant
chemotherapy with cisplatin and vinorelbine is one standard-of-care. We sought to determine in a preclinical model whether
(a) the combination of cisplatin and vinorelbine could positively modulate components of the immune system independent of
antitumor activity, and (b) there were synergistic effects of this drug combination and vaccine immunotherapy. We examined
the effect of cisplatin/vinorelbine on gene expression, cell-surface phenotype, and CTL-mediated cytolysis of murine lung
carcinoma cells in vitro; we also assessed the effects of cisplatin/vinorelbine on immune subsets and function of Tregs in
vivo. Finally, we evaluated the potential synergy between chemotherapy and a recombinant yeast-CEA vaccine in a murine model
transgenic for CEA with mice bearing lung tumors. These studies demonstrate that exposure of lung tumor cells to the platinum
doublet cisplatin/vinorelbine modulates tumor cell phenotype and increases sensitivity to CTL-mediated cytolysis. These studies
also demonstrate that cisplatin/vinorelbine (a) induces sub-myeloablative leucopenia that differentially modulates reconstitution
of Treg versus effector T-cell subsets and (b) can be employed synergistically with vaccine, exploiting homeostatic peripheral
expansion of T cells. Antitumor studies show for the first time that cisplatin/vinorelbine combined with vaccine increases
the survival of mice with established NSCLC. These findings provide the rationale for the potential clinical benefit of the
combined use of vaccine with cisplatin/vinorelbine chemotherapy regimens. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|