Therapeutic Efficacy of Antigen-Specific Vaccination and Toll-Like Receptor Stimulation against Established Transplanted and Autochthonous Melanoma in Mice

Abstract

Malignant melanoma is an attractive model disease for the development of antigen-specific immunotherapy because many antigens recognized by tumor-specific T cells have been identified. In C57BL/6 mice, genetic immunization with recombinant adenovirus encoding xenogeneic human tyrosinase-related protein 2 (Ad-hTRP2) induces protective but not therapeutic cellular immunity against growth of transplanted B16 melanoma cells. Here, we additionally applied CpG DNA and synthetic double-stranded RNA, which activate the innate immune system via Toll-like receptors (TLR). Both adenoviral vaccination and peritumoral injections of TLR ligands were required for rejection of established B16 melanoma in the skin. To more closely mimic the clinical situation in patients with melanoma, we evaluated this combined immunotherapeutic strategy in genetically modified mice, which overexpress hepatocyte growth factor (HGF) and carry an oncogenic mutation in the cyclin-dependent kinase 4 (CDK4) R24C . HGF Â CDK4 R24C mice rapidly develop multiple invasive melanomas in the skin following neonatal carcinogen treatment, which spontaneously metastasize to lymph nodes and lungs. Vaccination with Ad-hTRP2 followed by injections of TLR ligands resulted in delayed growth of autochthonous primary melanomas in the skin and reduction in the number of spontaneous lung metastases but did not induce tumor regression. Carcinogen-treated HGF Â CDK4 R24C mice bearing multiple autochthonous melanomas did not reject transplanted B16 melanoma despite treatment with Ad-hTRP2 and TLR ligands, suggesting the development of tumor immunotolerance. Further investigations in our novel genetic melanoma model may help to better understand the role of the immune system in the pathogenesis and treatment of this life-threatening disease.

Whole recombinant yeast vaccine induces antitumor immunity and improves survival in a genetically engineered mouse model of melanoma

“…39 have shown that combined immunotherapy with vaccination and adjuvant injection delays melanoma growth, in concordance with our data. By further adding cyclophosphamide and adoptive transfer of tumor-specific T lymphocytes into these regimens, Kohlmeyer et al 40 have shown that a combination chemoimmunotherapy results in complete regression of both primary and metastatic melanoma in the Hgf-Cdk4 R24C melanoma mouse model.…”

Therapy of established B16-F10 melanoma tumors by a single vaccination of CTL/T helper peptides in VacciMax®

“…CD4 + T-cell help is essential for the differentiation and expansion of CTLs [35], as well as their maturation into functional memory CTLs [36]. To achieve CD4 + T-cell help, a universal T helper epitope, PADRE was used in VM [37].…”

Growth, metastasis, and expression of CCL2 and CCL5 by murine mammary carcinomas are dependent upon Myd88

“…In fact, studies have reported both beneficial and detrimental effects following treatment with TLR agonists. For instance, Hirabayashi et al, [6] reported that Poly(I:C), a TLR3 agonist, could slow the growth of a panel of tumors including the commonly used breast cancer cell lines MCF7, T47D, MDA-MB-468, MDA-MB-453 and SKBR3, whereas a panel of normal cell lines were unaffected, and Tormo et al, [7] reported that Poly(I:C) and CpG ODN in combination with an adenoviral vector encoding tyrosinase-related protein 2 (TRP2) could delay growth of the B16 melanoma. On the other hand, Huang et al, [8] reported that the MC26 murine colon carcinoma responded to LPS in a manner that inhibited anti-tumor immunity.…”