Priming of T cells with aAd-transduced DC followed by expansion with peptide-pulsed DC significantly enhances the induction of tumor-specific CD8+ T cells: implications for an efficient vaccination strategy

Abstract

In recent years, vaccination strategies using antigen-presenting cells (APC) have been under investigation. Antigen delivery using genetic immunization through ex vivo transduction of dendritic cells (DC) is supposed to enhance the induction of antitumor responses in humans by activating a broad range of peptide-specific CD8 + T cells. In this study, we compared the potential of adenoviral (Ad)-transduced versus peptide-pulsed DC to induce melanoma-antigen (Ag)-specific T-cell responses in vitro. Whereas gp100-peptidepulsed DC induced long-lasting specific CD8 + T-cell responses against single peptides, Ad-transduced DC induced broad and strong, specific immunity against various peptides of the gp100-Ag. Surprisingly, several restimulations led to decreasing gp100-specific and in parallel to increasing antiadenoviral T-cell responses. Nevertheless, those anti-adenoviral T-cell responses provided an 'adjuvant' effect by inducing an early release of high amounts of IL-2/IFN-g, therewith enhancing CTL induction in the initiation phase. Based on these data, we suggest a prime/boost vaccination strategy in melanoma patients -combining the use of Ad-DC and peptide-pulsed DC -to obtain efficient and long-term antitumor T-cell responses.

Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity

“…Using a DC cell line, Brossart et al (43) showed that DCs transfected with adenoviral vector or vaccinia virus expressing the SIINFEKL peptide induce stronger in vitro stimulation of CTL activity than peptide-pulsed DCs. In contrast, Tuettenberg et al (32) recently showed that adenoviral vector-transduced DCs only induced short-lived immune responses compared with Ag-pulsed DCs in vitro. The evidence suggests that the generation of vector-specific immune responses through repeated stimulation by adenoviral vector-transduced DCs may interfere with the development and potency of the desired Ag-specific T cell responses (32).…”

“…In contrast, Tuettenberg et al (32) recently showed that adenoviral vector-transduced DCs only induced short-lived immune responses compared with Ag-pulsed DCs in vitro. The evidence suggests that the generation of vector-specific immune responses through repeated stimulation by adenoviral vector-transduced DCs may interfere with the development and potency of the desired Ag-specific T cell responses (32). Nonviral transfection of DCs would obviate this obstacle, and the delivery of Ag-encoding mRNA to DCs has been shown to result in Ag expression and stimulation of Ag-specific T cell responses (61,62).…”

“…Although, in theory, presentation of endogenously expressed Ag by gene-modified DCs should elicit more potent immune responses than peptide-or protein-pulsed DCs, results from comparative investigations are conflicting (32,(43)(44)(45). This may be a critical issue for immunotherapy, particularly in the setting of tumor-bearing hosts or victims of viral infections such as HIV, in whom immunizations will need to overcome pre-existing immunosuppressive mechanisms.…”

“…However, recent data indicate that adenoviral transduction results in DC maturation and proinflammatory cytokine production through activation of the NF-B pathway (31). In addition, Ags derived from adenoviral proteins can be presented by transduced DCs, resulting in not only the interference of the desired Ag-specific immune responses, but also the induction of vectorspecific immunity that makes repeated immunization problematic (32). Oncoretroviral vectors have been used to deliver genes into DCs with minimal interference of their function, but low transduction efficiencies, presumably due to the fact that oncoretroviral vectors are unable to transduce nondividing cells, limit their applications (33).…”

Modulation of viability and maturation of human monocyte‐derived dendritic cells by oncolytic adenoviruses

“…Supportive of our hypothesis are (i) recent reports for other oncolytic viruses, which have shown that their anti-tumor efficacy in part or even to a large extent is mediated by anti-tumor immunity rather than direct viral cell lysis [13][14][15][16][17] and (ii) the observation, in genetic vaccination studies using replication-deficient adenoviral vectors, that anti-viral immune activation has adjuvant activity for immunity to tumor antigens. 18 Importantly, strategies for transgene expression by oncolytic adenoviruses facilitate the modulation and potentiation of viral oncolysis-induced anti-tumor immune responses by expression of immunoregulatory factors. 4 The question as to whether potent anti-cancer immune responses are induced by adenoviral oncolysis has not been addressed adequately to date.…”