Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.

Abstract

To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, longlasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.

Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

“…Some success has been achieved with this approach. 3,4,18 Relevant to this report, Dranoff et al 19 included GM-CSF in a panel of 10 molecules to compare their ability to enhance the immunogenicity of tumor cells. In the B16 melanoma model, nontransduced cells possessed little ability to stimulate systemic antitumor immunity.…”

Gene transfer approaches in cancer immunotherapy

“…Later, this approach was significantly improved by Lindenmann and Klein. 14 21 granulocyte colony-stimulating factor (G-CSF), 22 granulocyte macrophage colony-stimulating factor (GM-CSF), 23 interferon (IFN)-g 24 and a wide list of other genes. It was not absolutely the best choice because an important step of innate immunity activation was missed and immunological mechanisms were directed straight up to CTL and DC activation to develop adaptive immune response, although it was very actively used during the decades.…”

“…Thus, a combination of these cytokines is a powerful tool, as it was reported. 65 The main cause of such amplifications of the immune GM-CSF Mouse models and clinical trial of autologous irradiated tumor cells generated by ex vivo transfection [23,63] Gene transfer approaches in cancer immunotherapy SS Larin et al system response is the involvement of different and independent mechanisms of adoptive immune response.…”

“…72,73 Mammalian Tag7/PGRP-S has been cloned from mouse, 69 human, 70 rat, 74 and cow. 75 There are small extracellular proteins (19)(20)(21)(22)(23)(24), which structurally share homology with T phage lyzozyme but do not possess any amidaze activity. Apart from their ability to recognize oligosaccharides and particularly peptidoglycan 70,75 cytotoxicity towards mammalian cells, 69,75,76 bactericidal and bacteriostatic activities 75 were detected.…”

Retroviral-mediated transfer of genes encoding interleukin-2 and interleukin-12 into fibroblasts increases host antitumor responsiveness

“…1 The antitumor activity of a number of cytokines has been demonstrated in various animal tumor models. [2][3][4][5] Interleukin-12 (IL-12) has attracted much enthusiasm in devising immunotherapeutic strategies. IL-12, a heterodimeric cytokine composed of two disulfide-linked subunits of ϳ40 and 35 kDa is naturally produced by activated antigen (Ag)-presenting cells.…”