Analysis and Characterization of Antitumor T-cell Response After Administration of Dendritic Cells Loaded With Allogeneic Tumor Lysate to Metastatic Melanoma Patients

Abstract

The primary goal of cancer vaccines is to induce CD8+ T cells specific for tumor-associated antigens (TAA) but the characterization of these cells has been difficult because of the low sensitivity of ex vivo assays. Here, we focused on TAA-specific CD8+ T-cell responses in melanoma patients after vaccination with autologous dendritic cells loaded with lysates derived from allogeneic tumor-cell lines (Lysate-DC). Out of 40 patients treated, 16 patients developed immune response to tumor-cell lysate and/or CD8+ T cells specific for differentiation and cancer-testis antigens. TAA-specific CD8+ T-cell responses were detected by interferon (IFN)-gamma enzyme-linked immunospot after in vitro sensitization and were, either transient during the treatment period or delayed, that is, observed after completion of all vaccinations. We could not correlate these immune responses to clinical data as none of the patients achieved an overall objective response according to Response Evaluation Criteria in Solid Tumors criteria. Three patients were reported as stable disease and 10 patients presented evidence of antitumor activity. We found that TAA-specific T cells characterized in 4 patients produced perforin ex vivo, but no IFN-gamma in enzyme-linked immunospot. Differential expression of IFN-gamma and perforin was also observed for viral-specific T cells. Altogether, our results show that Lysate-DC therapy elicited tumor-specific CD8+ T cells nonlimited to human leukocyte antigen-A2+ patients, with some T cells secreting perforin ex vivo and IFN-gamma only after restimulation. The differential expression of perforin and IFN-gamma by antitumor and antiviral CD8+ T cells supports that the sole use of IFN-gamma production to monitor T cells overlooks functional T-cell subpopulations triggered by vaccines.

Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response

“…For the recall response against viruses, cells were similarly cultured with the mix of 32 peptides from cytomegalovirus, influenza virus, and Epstein-Barr virus (CTL). After 1 week of cell culture, the presence of UCP-specific T cells was measured by IFN-g ELISPOT as detailed above (30)(31)(32).…”

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

“…Likewise, CTLs with lytic activity that do not secrete IFNg have been reported by several other research groups. 34,35 Indeed, IFNg and cytotoxicity are regulated independently in CD8 C T cells. 34 Many previous studies with CC-DC fusion vaccines mentioned an overnight incubation of the fusion mixture.…”

Immunothérapie des cancers

“…L'utilisation de peptides longs comprenant des épito-pes peptidiques reconnus par les lymphocytes CD4 + et CD8 + , de virus recombinants avec les ADNc codant pour des antigènes tumoraux ou de cellules dendritiques sensibilisées avec des lysats tumoraux ou des peptides, s'est avérée efficace pour induire des réponses lymphocytaires T CD8 + antitumorales dans des essais cliniques chez l'homme, qui sont parfois associées à des réponses cliniques. Néanmoins, chez des patients atteints de cancers métastatiques, cette induction lymphocytaire est souvent transitoire [37,38]. Pour minimiser les risques d'immunisation contre le vecteur viral, des stratégies de type prime-boost utilisant deux vecteurs viraux recombinants différents codant pour le même antigène ont été développées avec un certain succès [31].…”