Antitumor Effect on Murine Renal Cell Carcinoma by Autologous Tumor Vaccines Genetically Modified with Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-6 Cells

Abstract

The authors evaluted the efficacy of vaccination with murine renal cell carcinoma (Renca) secreting the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene and interleukin-6 (IL-6) gene for the treatment of Renca tumor. Murine GM-CSF and murine IL-6 genes were introduced and expressed in Renca cells (Renca-GM-CSF and Renca-IL-6). For a prevaccination study, wild-type Renca cells were injected subcutaneously into Balb/c mice that had been vaccinated three times with inactivated wild-type Renca, Renca-GM-CSF, Renca-IL-6, or a mixture of Renca-GM-CSF and Renca-IL-6 cells 7, 14, and 21 days before this tumor inoculation. For vaccination experiments, Renca tumor-bearing (8 to 10 mm) mice were injected subcutaneously weekly for 3 weeks with inactivated wild-type Renca cells, or either one or a combination of Renca-GM-CSF and Renca-IL-6. A nonvaccinated control was included in all experiments. The animals were monitored for survival and tumor development for 8 weeks. Mice inoculated with wild-type Renca alone died from the tumor within 35 days. Renca-IL-6 grew slower than wild-type Renca (p < 0.05). No tumor was produced by Renca-GM-CSF. Prevaccination with the combination of Renca-GM-CSF and Renca-IL-6 prevented subsequently inoculated wild-type Renca from forming tumors, and prevaccination with either one of them, compared with prevaccination with wild-type Renca, retarded tumor growth and prolonged survival time. Tumor-bearing mice vaccinated with wild-type Renca died within 42 days. Vaccination with Renca-GM-CSF or Renca-IL-6 alone prolonged the survival time, but only Renca-GM-CSF drastically reduced the tumor size. Vaccination with the combination of them achieved complete remission. Neither of the cytokine-secreting cells enhanced the expression of MHC class I or II molecules. Autologous tumor cell vaccine secreting GM-CSF is effective in preventing and treating established tumors. Its efficacy is enhanced by the cosecretion of IL-6.

4-1BB-Specific Monoclonal Antibody Promotes the Generation of Tumor-Specific Immune Responses by Direct Activation of CD8 T Cells in a CD40-Dependent Manner

“…However, immunity can be generated against these same tumors using a variety of preimmunization strategies such as simple implantation/excision strategies (4 -6). These results demonstrate that priming of tumorreactive T cells occurs in normal, unmanipulated mice and imply that in many cases tumor growth may be due to inefficient or incomplete activation of effector T cells (7)(8)(9)(10)(11).…”

“…family member (CD40L) yields cooperative effects (29). To determine whether combined treatments of Flt3L and 4-1BB (M6) would result in enhanced tumor rejection, C57BL/10 mice were implanted with the B10.2 tumor and treated with a suboptimal regimen of Flt3L (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and/or injected with 41BB (M6) mAb on days 13 and 16. Treatment with either Flt3L or 4-1BB (M6) resulted in tumor rejection in a proportion of mice (40 and 80%, respectively), but combining Flt3L and 4-1BB (M6) treatments resulted in rejection of tumors in 100% of the test mice and at a faster rate than in mice treated with either agent alone (Fig.…”

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

“…Accordingly, the treatment of minimal disease with cancer vaccines has been tested in hundreds of preclinical studies in animal models with small amounts of tumor burden (6,(9)(10)(11)(12)(13). These preclinical studies have translated to several trials of cancer vaccines to prevent recurrences in patients after surgery (6,12).…”

Highly Successful Therapeutic Vaccinations Combining Dendritic Cells and Tumor Cells Secreting Granulocyte Macrophage Colony-stimulating Factor

“…Vaccination with tumor cells engineered to secrete GM-CSF has been shown to be an effective adjuvant, mainly because it enhances antigen processing and presentation by recruiting locally large numbers of antigen-presenting cells (30,31). However, if GM-CSF gene-engineered cell vaccines were quite effective at protecting animals from a parental tumor injection (32,33), they were recorded poorly effective against established tumors (9). By coinjecting dendritic cells with irradiated GM-CSF-secreting 9L cells, we have greatly increased the induction of specific and systemic therapeutic immune responses and thereby the long-term survival rate of the rats (from 8 to 60%, P Ͻ 0.0001).…”