Adenoviral Vectors Expressing Lymphotactin and Interleukin 2 or Lymphotactin and Interleukin 12 Synergize to Facilitate Tumor Regression in Murine Breast Cancer Models

Abstract

We have previously demonstrated that intratumoral injection with Ad vectors expressing IL-2 or IL-12 can induce regression in a murine breast cancer model. These IL-2- or IL-12-induced antitumor responses were mainly mediated by Ag-specific T cells. Lymphotactin is a novel lymphocyte chemokine that can cause local accumulation of CD4+, CD8+, and NK cells. We hypothesized that addition of lymphotactin may enhance the antitumor immune responses induced by locally produced IL-2 and IL-12 as we have previously shown. To this end we constructed two double-recombinant adenoviral vectors expressing lymphotactin along with either IL-2 (Ad5 Lym/IL-2) or IL-12 (Ad5 Lym/IL-12). Subcutaneous injection of polyoma middle T (PyMT) or Neu (8142) transgenically derived breast adenocarcinoma cells, in the hind flank of FVB/n mice, results in the formation of tumor nodules in 14-21 days. We show that these constructs elicit potent antitumor responses when administered intratumorally. The antitumor responses are long lasting as determined by rechallenge experiments and hence demonstrate a protective immunity. These observations indicate that by augmenting the antitumor response with adenoviral vectors expressing lymphotactin in combination with IL-2 or IL-12 is a novel way to enhance immunotherapeutic approaches.

Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

“…29 RANTES and lymphotactin also inhibited tumor formation and generated tumor immunity. [30][31][32] MCP-1 was shown to reduce in vivo growth of tumor cells and to increase infiltration of macrophages/monocytes to the tumor site. 33 Recently, intratumoral injection of recombinant SLC showed potent antitumor response and led to tumor eradication in treated mice.…”

Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively, synergizes to facilitate regression of established tumors

“…20 Recently, Emtage et al have shown that adenoviral vectors expressing lymphotactin and IL -12 enhanced tumor regression in murine breast cancer models. 21 More recently, Narvaiza et al have reported that intratumoral coinjection of two adenoviruses, one encoding the chemokine IP -10 and another encoding cytokine IL -12, resulted in marked antitumor synergy. 22 In this study, we constructed two recombinant adenoviral vectors AdVIL-18 and AdVIP -10 expressing the functional IL -18 and IP-10 molecules, respectively, and investigated the antitumor effects by intratumoral injection of these two adenoviral vectors into established J558 tumors in animal models.…”

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.…”