Combined CXC chemokine and interleukin-12 gene transfer enhances antitumor immunity

Abstract

It has been shown that intratumor administration of an adenovirus vector expressing IL-12 produces a potent T cellmediated response that leads to significant tumor regression in a murine breast cancer model. IP-10 and MIG are CXC chemokines that recruit mononuclear cells in vivo. In addition to their chemotactic roles, IP-10 and MIG inhibit angiogenesis. We tested whether the addition of IP-10 or MIG may both enhance the antitumor immune response of IL-12 through T cell recruitment and inhibit tumor growth through angiostasis. Adenovirus vectors expressing IP-10 or MIG and/or IL-12 were administered intratumorally in a

Oestradiol enhances tumour regression induced by B7-1/IL-2 adenoviral gene transfer in a murine model of breast cancer

“…As previously shown, the cytokines delivered intratumorally did mediate an effective immune response and tumour regression, whereas systemic delivered cytokines fail to induce any tumour response (Addison et al, 1995). The tumour size, 160728 mm 3 for placebo tumours and 228760 mm 3 E2-treated tumours, was in the range previously described by our lab using B7-1/IL-2 and other cytokines delivered to PyMT tumours by adenoviral vectors (Addison et al, 1998;Emtage et al, 1998;Palmer et al, 2001).…”

“…Specific PyMT antigen cytotoxic T-cell killing was measured as previously described (Addison et al, 1998;Palmer et al, 2001). Briefly, splenocytes were obtained from mice whose tumours had regressed and had also resisted rechallenge and were restimulated for 5 days by coculture with irradiated 516MT3 cells that express the PyMT antigen.…”

Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

“…26 Two other attempts at using adenovirusdelivered IP-10 to treat mammary and colorectal adenocarcinomas and fibrosarcoma showed that IP-10 had moderate antineoplastic activity on its own, but a striking ability to potentiate antitumor reactions initiated by IL -12 or T-cell adoptive therapy. 24,25 The latter observation allows to suggest that the ability of IP -10 to foster ongoing immune reactions could be responsible for MVMp / IP-10-induced suppression of H5V hemangiosarcomas. It is known that lesions arising from H5V cells are immunogenic and serve as targets for a host defense reaction, which allows tumors of a small or medium size to be eradicated, but becomes overwhelmed and fails to prevent tumor recurrence when primary implants are too large.…”

“…This strategy is further supported by the fact that no deleterious side effects associated with IP-10 applications have been reported so far (present investigation and Refs. [20][21][22][23][24][25][26]). …”

New insights into IL-12-mediated tumor suppression

“…71,74 Nevertheless, synergistic antitumor responses in breast cancer have been achieved by combining local adenovirus-mediated gene transfer of IL-12 with T-cell chemoattractants (lymphotactin, CXCL10), costimulatory molecules (B7.1, glucocorticoid induced TNF receptor ligand, 4-1BB ligands), GM-CSF, radiotherapy or antiangiogenic therapy. [77][78][79][80][81][82][83] Furthermore, the combination with chemotherapeutic or antiangiogenic agents in lung, skin and colorectal cancer, or with antiangiogenic agents in prostate cancer proved to be more efficient than viral-mediated IL-12 gene therapy alone in different types of tumors. [84][85][86][87][88][89] Even though local delivery of IL-12 by gene therapy resulted in a more sustained expression of IL-12 in comparison with the levels obtained by injecting the recombinant protein, the lack of selectivity and the occurrence of non-specific immune responses associated with the use of viral vectors remain a major concern when using this strategy to deliver IL-12.…”