Complete tumour regressions induced by vaccination with IL-12 gene-transduced tumour cells in combination with IL-15 in a melanoma model in mice

Abstract

In the present study, IL-12 gene-transduced B78-H1 melanoma cells (B78/IL-12) were used in combination with IL-15 to treat melanoma-bearing mice. Genetically modified B78/IL-12 cells, when injected subcutaneously, induced strong activation of antitumour mechanisms resulting in complete loss of tumourigenicity. In a therapeutic model, intratumoural injection of irradiated B78/IL-12 cells significantly delayed tumour growth and led to the regression of melanoma in one case. Similarly, consecutive daily injections of IL-15 markedly inhibited tumour progression with occasional curative effects. When used in combination, vaccination with B78/IL-12 cells and treatment with IL-15 caused eradication of established tumours in all treated mice. The combined treatment with B78/IL-12 cells and IL-15 activated not only a local response against tumour, but also induced systemic antitumour immunity that led to a delay or inhibition of tumour development at a distant site. In vitro studies demonstrated that when used together, B78/IL-12 cells and IL-15 induced a shift from a type Th2 to a type Th1 response. Activation of the antitumour immune response in double-treated mice resulted, in part, from stimulation of IFN-gamma production and was accompanied by the development of cytotoxic effectors in the spleen. As shown in a macrophage tumouricidal assay, macrophages could also play a role in the antitumour effects. The results confirmed that vaccination with IL-12 gene-modified tumour cells is superior to the treatment with unmodified tumour cell vaccine and, additionally, showed that IL-15 is an excellent candidate for adjuvant therapy, inducing synergistically not only a delay of tumour growth but also its complete eradication.

Interleukin 12: still a promising candidate for tumor immunotherapy?

“…Classical examples of such cytokines are TNF-α [45, 46], IL-2 [47, 48], IL-15 [49, 50], IL-18 [50, 51], or GM-CSF [52]. Interesting observations have also been made regarding the actions, either positive or negative, of IL-12 on hematopoiesis [53–55], which can be of importance in cancer patients as well.…”

“…injectionColon 26 adenocarcinomaIL-12-encoding plasmid in liposomes; distant injection[106]Angiostatin; i.d. injectionB16F10 melanomaIL-12-encoding plasmid; intratumoral injection[107]rIL-2; systemic administrationMCA-105 sarcoma, MC-38 adenocarcinomaIL-12-producing fibroblasts; intratumoral injection[47]IL-2 in adenoviral vector; intratumoral injectionMammary adenocarcinomaIL-12 in adenoviral vector; intratumoral injection[108]rIL-15; local administrationB78-H1 melanomaIL-12-producing tumor cells; intratumoral injection[49]IL-18; distant injection of IL-18-producing tumor cellsSCK mammary carcinomaIL-12-producing tumor cells; distant injection[109]IL-27; distant injection of IL-27-encoding plasmidCT26 adenocarcinoma 4T1 adenocarcinomaIL-12-encoding plasmid; distant injection[110]IP-10 in adenoviral vector; intratumoral injectionPyMT-induced mammary adenocarcinoma, MCA 207 sarcomaIL-12 in adenoviral vector; intratumoral injection[111]Lymphotactin in adenoviral vector; intratumoral injectionPyMT- or Neu-expressing mammary adenocarcinomaIL-12 in adenoviral vector; intratumoral injection[112]CD80 in adenovirus vector; intratumoral injectionMT1A2 mammary adenocarcinomaIL-12 in adenovirus vector; intratumoral injection[113]Agonistic anti-CD137 agonistic antibody; systemic administrationB16-OVA melanoma, TC-1 lung carcinomaIL-12 in SFV vector[114]CD137 ligand 10 in adenoviral vector; intratumoral injectionMCA26 colon carcinomaIL-12 in adenoviral vector; intratumoral injection[115]…”

“…In another model, distant injection of IL-12- and IL-27-encoding plasmids resulted in eradication of CT26 tumor in all treated mice [110] and intratumoral injection of IL-12 gene-transduced B78-H1 melanoma cells in combination with IL-15 similarly cured all treated mice [49]. Synergistic interaction of IL-12 gene therapy was also observed with B7.1 (CD80) injected intratumorally in an adenoviral vector [113].…”

Antiproliferative Properties of Type I and Type II Interferon

“…Of medical importance would be a demonstration of this strong antitumor activity in animal models and whether established tumors can be eradicated [115,117]. Also important would be identification of the mechanisms responsible for the higher sensitivity of many tumor cells over diploid cells [109].…”

Immune correlates of melanoma survival in adoptive cell therapy

“…T H 1 cells play a protective role in antitumor immunity in animal models by enhancing the cytolytic activity of CD8 + cells, whereas—according to most reports—T H 2 cells contribute to tumor progression 63 , 64 . Similar findings have been reported in the human setting, in which CTL responses were enhanced by T H 1 and T H 0 cells, but not by T H 2 cells 65 .…”