Type I IFN innate immune response to adenovirus-mediated IFN-γ gene transfer contributes to the regression of cutaneous lymphomas

Abstract

IntroductionPrimary cutaneous lymphomas (CLs) represent the second most common extranodal group of non-Hodgkin lymphomas and are characterized by an accumulation of clonal T or B lymphocytes preferentially homing to the skin (1). Most CLs are indolent diseases with good prognosis that display a chronic course, sometimes progressing over decades. This in turn creates an increasing need for treatment modalities that would effectively control the disease for a longer time period together with showing good tolerability. Immunotherapy is one such solution that currently belongs to the standard therapeutic armamentarium. The use of recombinant cytokines has found its rationale in the immunobiology of this disease group and aims to enhance antitumor immunity (1, 2). As an alternative to recombinant cytokines that are often associated with significant systemic side effects, we recently described adenovirusmediated (Ad-mediated) delivery of human IFN-γ gene directly into CL lesions, showing good tolerability together with promising efficacy (3). Adenoviral vectors belong to the most frequently used gene delivery systems due to their ability to transduce a broad spectrum of cells and package large sequences and their low production costs (4). The fact that they do not integrate into the host genome has made them attractive in cancer immunotherapy, where only

European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas

“…Controlled multicenter studies are also required to assess the efficacy of new therapies, such as yttrium-90 ibritumomab tiuxetan (Zevalin) or 131I-tositumomab (Bexxar) radioimmunotherapy 97 and pegylated liposomal doxorubicin 98 (plus rituximab) in PCLBCL, LT and gene therapy with adenovirus-mediated transfer of IFN-␥ in PCFCL and PCMZL. [99][100][101] Today, only the last mentioned approach is investigated in a prospective trial. Finally, patients with a CBCL can best be managed in centers where a close collaboration between dermatologist, hematologist/ oncologist, and radiation oncologist exists.…”

β2microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients

“…B2M is known as a classic IFN-responsive gene (Yan et al, 2004;Gottenberg et al, 2006;Gray et al, 2006;Joyce et al, 2007;Scherbik et al, 2007;Urosevic et al, 2007). Interferons were originally discovered as antiviral proteins that inhibit virus replication (Isaacs and Lindenmann, 1987).…”

Adenovirus-triggered innate signalling pathways

“…The Ad entry-mediated production of type I IFNs has been recognized only recently. The importance of IFN-αβ production was indicated by clinical trials with oncolytic Ads, where a better prognosis was associated with situations in which recombinant Ad vectors induced robust IFN-αβ responses [104]. While pDCs can recognize Ad DNA via TLR9 in vitro [71,72,80], in vivo studies in Ad-infected mice have shown that the majority of IFN-αβ is produced in myeloid DCs (Fig.…”