The immune anti-tumor effects of GM-CSF and B7-1 gene transfection are enhanced by surgical debulking of tumor

Abstract

Malignant mesothelioma ( MM ) is a solid tumor largely unresponsive to conventional therapies. Immunological gene therapy shows promise in murine models and human clinical trials; however, the role of surgery in combination with gene therapy has not been widely studied. The aim of this study was to determine if debulking surgery improved the effectiveness of gene therapy in a murine MM model. Mice were subcutaneously inoculated with the MM cell line, AC29, at two different sites, 4 days apart, to allow a surgical and distal site tumor to develop. Once tumors were established, the surgical site tumor was debulked and vaccination of syngeneic tumor transfectants encoding genes for IL -4, IL -2, GM -CSF, B7 -1 or allogeneic MHC molecules commenced at a site away from both tumors, and tumor growth was measured. Neither debulking surgery nor gene therapy alone delayed tumor growth. However, there was a clear delay of tumor growth when debulking surgery was combined with vaccination of tumor transfectants expressing B7 -1 or high levels of GM -CSF. Combinations of these two transfectants did not lead to a synergistic effect. This study demonstrates that debulking surgery can augment the immunostimulatory effects of immunological gene therapy and can delay tumor growth. This has implications for the future design of human gene therapy trials for solid tumors such as MM.

Induction of T-Cell Apoptosis in Rats by Genetically Engineered Glioma Cells Expressing Granulocyte-Macrophage Colony-Stimulating Factor and B7.1

“…challenge with wild-type tumor cells than the vaccine expressing either molecule alone (38). On the other hand, some studies reported that such combinations had no synergistic or enhanced antitumor effects on melanoma, squamous cell cancer, or malignant mesothelioma models (19,36,37). Collectively, all of these reports show that the antitumor effects of combining GM-CSF and B7.1 were either enhanced or kept the same as single gene therapy; yet, our results showed the opposite.…”

“…Previous studies attributed the lack of enhanced antitumor effects by GM-CSF and B7.1 combination therapies to the following reasons: (a) inhibitory activity of these immune factors with each other, (b) dosage of inoculated tumor cells, (c) low immunogenicity of tumor cells, and (d) absence of MHC on tumor cells (19,37). All these factors might contribute to the reduced antitumor effects of the GM-B7.1/RT-2 tumor vaccine observed in our tumor model.…”

Gene therapy for malignant mesothelioma: beyond the infant years

“…68 In preclinical studies, this recombinant showed enhanced efficacy in combination with debulking surgery, chemotherapy (gemcitabin and cisplatin), or cyclooxygenase-2 inhibition. 1,71,72 A similar synergy was seen when GM-CSF or B7.1 gene therapy was combined with debulking surgery 67 or when IFN-a treatment was combined with chemotherapy. 73 The fact that IFN-a and -b stimulate crosspriming of CD8 þ T cells, 74 suggests that this immune priming step may be rate-limiting in the efficacy of conventional treatments.…”

Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma

“…Target cells were labeled with 51 Cr by incubating 3 ϫ 10 cells in a 6-well plate with 3.7 MBq of 51 Cr (New England Nuclear, Wellesley, MA) in culture medium for 18 hr and were then washed 3 times with PBS. Varying numbers of effector cells were mixed with target cells to yield E:T ratios of 60:1 to 7.5:1.…”