Administration of IFN-α Enhances the Efficacy of a Granulocyte Macrophage Colony Stimulating Factor–Secreting Tumor Cell Vaccine

Abstract

IFN-A is approved for the treatment of multiple cancers. Its pleiotropic properties include inhibition of proliferation and angiogenesis and induction of apoptosis. Type I IFNs also exert immunomodulatory effects, which make it an appropriate candidate to combine with cancer vaccines. The studies reported herein show that 50% of mice reject established B16 tumors following treatment with the combination of a granulocyte macrophage colony-stimulating factor-secreting tumor cell vaccine (B16.GM) and subclinical doses of recombinant murine IFN-A delivered at the vaccine site. Similarly, 80% of mice treated with the combination reject established B16 tumors when recombinant murine IFN-A is given at the challenge site, suggesting that in the latter case its antiproliferative, proapoptotic, and antiangiogenic properties may be involved in controlling tumor growth. In contrast, fewer than 10% of mice reject the tumors when either one is used as a monotherapy. Furthermore, a 30-fold increase in the frequency of melanoma-associated antigen (Trp-2 and gp100) specific T cells was observed in mice treated with the combination when compared with unvaccinated controls. These data show that IFN-A combined with a granulocyte macrophage colonystimulating factor-secreting tumor cell vaccine significantly enhances vaccine potency and may represent a potential new approach for tumor immunotherapy. (Cancer Res 2005; 65(6): 2449-56)

Recombinant Newcastle disease virus (NDV) with inserted gene coding for GM-CSF as a new vector for cancer immunogene therapy

“…36 Also a combination of IFN-a and GM-CSF secreting tumor vaccine was shown to significantly enhance the potency of the immunotherapeutic effect. 37 The expression of the HN protein of NDV at the cell surface of the ATV-NDV tumor vaccine 5 as well as the replication of NDV within these cells may be of central importance for the induction of IFN-a at the vaccination site and consequently for the observed antitumor response in clinical studies based on NDV tumor vaccine. 16 Here, we show that a tumor vaccine obtained by irradiation and infection with rec(GM-CSF) induces a stronger IFN-a response in human monocytes and PDCs than a vaccine infected with the virus without incorporated foreign gene.…”

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

“…10 GM-CSF-based immunotherapy has been shown to increase the survival in several experimental rat and mouse glioma models. 3,4,11,12 Peripheral vaccination with GM-CSF is evaluated in several clinical trials for various types of cancer, [13][14][15] and so far preliminary results have shown low toxicity and activation of an immune response. IFNg is a multifunctional cytokine that recently has been linked to immune surveillance of developing tumors.…”

A Kunjin replicon vector encoding granulocyte macrophage colony-stimulating factor for intra-tumoral gene therapy

“…We propose that the efficiency of this treatment modality arises from the synergy between GM-CSF production and IFN-a/b induction for induction of anti-cancer CD8 T cells. 24,36,37 As with most intra-tumoral gene delivery systems, the level of transfection in vivo is likely to be an important factor. 4 We have tested the transfection efficiency of a number of tumour cell lines in vitro and found that at MOI ¼ 10, 1-5% of CT26 cells and 10-20% of B16-OVA cells are transfected, with Vero and BHK cell transfection usually reaching 50-90% (data not shown).…”

“…2 Dendritic cell attraction and maturation appear to be the critical components of GM-CSF's mechanism of action, 21,22 with tumour destruction largely dependent on anti-cancer CD8 T cells. 20,[23][24][25] IFN-a/b is approved for the treatment of several cancers and mediates a range of direct activities against cancers, the best known of which are slowing of the cell cycle, promotion of differentiation, anti-angiogenesis and promotion of apoptosis. 26 IFN-a/b is also an important link between the innate and adaptive immune systems.…”

“…36,37 Therapy with a GM-CSF-secreting tumour cell vaccine was also shown to be substantially enhanced when IFN-a was injected into the tumour site, with the improved therapy associated with increased anti-cancer CD8 T cells. 24 Herein we sought to exploit the synergy between IFN-a/ b and GM-CSF for intra-tumoral gene therapy by constructing a Kunjin replicon vector encoding GM-CSF. A mutation was also introduced into the vector's non-structural protein NS2A ( 30 Ala to 30 Pro), which was expected to increase the level of IFN-a/b production by replicon-transfected cells.…”