Requirement for IFN-γ, CD8+ T Lymphocytes, and NKT Cells in Talactoferrin-Induced Inhibition of neu+ Tumors

Abstract

We have previously shown that talactoferrin-alfa (TLF), a recombinant human lactoferrin, is an immunomodulatory protein that is active against implanted tumors, both as a single agent and in combination with chemotherapy. In this study, we show that talactoferrin is active against autochthonous tumors in a transgenic mouse line, which is more analogous to human cancers, and identify key mechanistic steps involved in the anticancer activity of oral TLF. BALB/c mice transgenic for the rat neu (ErbB2) oncogene (BALBneuT) treated with oral TLF showed a significant delay in carcinogenesis, with 60% tumor protection relative to vehicletreated mice at week 21. Oral TLF also showed tumor growth inhibition in wild-type BALB/c mice implanted with neu + mammary adenocarcinoma, with one third displaying a longlasting or complete response. Oral TLF induces an increase in intestinal mucosal IFN-; production and an increase in Peyer's patch cellularity, including expansion of CD8 + T lymphocytes and NKT cells, and the enhancement of CD8 + Tcell cytotoxicity. In IFN-; knockout mice, there is an absence of the TLF-induced Peyer's patch cellularity, no expansion of CD8 + T lymphocytes and NKT cells, and loss of TLF anticancer activity. TLF antitumor activity is also lost in mice depleted of CD8 + T cells and in CD1 knockout mice, which lack NKT activity. Thus, the inhibition of distant tumors by oral TLF seems to be mediated by an IFN-;-dependent enhancement of CD8 + T-and NKT cell activity initiated within the intestinal mucosa. [Cancer Res 2007;67(13):6425-32]

Lactoferrin Acts as an Alarmin to Promote the Recruitment and Activation of APCs and Antigen-Specific Immune Responses

“…Therefore, lactoferrin is a promising adjuvant for use in cancer vaccines, because Th1 immune response is required for tumor rejection. In this regard, TLF has been shown to increase IFN-␥ production and cytotoxic capacity of T lymphocytes in tumor-implanted mice (33).…”

“…More recently, TLF, a recombinant hLF has been shown to suppress the growth of implanted tumors in mouse models (16,33) and to exhibit antitumor activity in phase I clinical trials (18). In this study, we have shown that TLF is able to: 1) chemoattract human monocytes in vitro and induce the recruitment of mouse phagocytes including neutrophils and monocytes/macrophages in vivo, 2) activate human APCs including monocytes/macrophages and DCs, 3) reduce human Treg content in cultured PBMCs, and 4) enhance Ag-specific mouse Th1 immune responses upon coadministration with the Ag.…”

Milk Derived Peptides with Immune Stimulating Antiviral Properties

“…In this study the anticancer activity of a recombinant form of human lactoferrin, talactoferrin-alfa (Agennix, Houston, TX) was evaluated. Talactoferrin-alfa was administered orally to BALB/c mice and the results showed an increase in the intestinal mucosal interferon-production, CD8+ T-cell cytotoxicity and the Peyer's patch cellularity which included expansion of CD8+ T lymphocytes and nature killer T-cells, whereas no such phenomena were showed in interferon-knockout mice [169]. Thus, the inhibition of friend virus complex infection and tumor growth by lactoferrin/talactoferrin-alfa seems to be mediated by an interferon--dependent enhancement of CD8+ T-cells and natural killer T-cell activity, leading to diversified functions like antiviral defence, immune activation and cell growth regulation [170][171][172][173].…”

Targeting the immune system for management of NSCLC: the revival?

“…To this end, talactoferrin has been assessed in clinical trials after evidence of antitumor activity against squamous cell and adenocarcinoma of the lung in animal models [71,84,85]. In a randomized phase II study, talactoferrin had activity against previously untreated stage IIIB or IV NSCLC in combination with paclitaxel and carboplatin, improving the response to chemotherapy alone (paclitaxel, carboplatin, and placebo) by 18 % for evaluable patients (29 to 47 %; p = 0.05) and by 15 % in the intent-to-treat population (27 to 42 %; p = 0.08) [86].…”