title: Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity.
abstract: In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity.
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, Switzerland. sophie.sierro@googlemail.com
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Sierro
authors.forename: Alena
authors.initials: A
authors.lastname: Donda
authors.forename: Rachel
authors.initials: R
authors.lastname: Perret
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Frédéric
authors.initials: F
authors.lastname: Levy
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007114:Immunization / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D016086:Lentivirus / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D000939:Epitopes; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; D003520:Cyclophosphamide; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase