An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells

Abstract

To develop a method to overcome the anergy that exists in tumor hosts to cancer, we have designed an adenoviral vector for the in vivo activation and tumor antigen loading of dendritic cells. This adenoviral vector encodes a fusion protein composed of an amino-terminal tumor-associated antigen fragment fused to the CD40 ligand (CD40L). Subcutaneous injection of an adenoviral vector encoding a fusion protein of the human papillomavirus E7 foreign antigen linked to the CD40L generates CD8 ؉ T cell-dependent immunoresistance to the growth of the E7-positive syngeneic TC-1 cancer cells in C57BL͞6 mice for up to 1 year. We also studied the s.c. injection of a vector carrying the gene for the human MUC-1 (hMUC-1) self-antigen fused to the CD40L. When this vector was injected into hMUC-1.Tg mice, which are transgenic for the hMUC-1 antigen, the growth of syngeneic hMUC-1-positive LL1͞LL2hMUC-1 mouse cancer cells was suppressed in 100% of the injected animals. The hMUC-1.Tg mice are anergic to the hMUC-1 antigen before the injection of the vector. These experimental results show that it is possible to use vector injection to activate a long-lasting cellular immune response against self-antigens in anergic animals. The vector-mediated in vivo activation, and tumorassociated antigen loading of dendritic cells does not require additional cytokine boosting to induce the immune response against the tumor cells. This vector strategy may therefore be of use in the development of immunotherapy for the many carcinomas in which the hMUC-1 antigen is overexpressed.(1) have used an oral plasmid DNA vaccine to induce immunological resistance to the engraftment of mouse colonic carcinoma cells that are positive for the human carcinoembryonic antigen (hCEA) gene in mice transgenic for hCEA. This plasmid encodes the extracellular domain (ecd) of the hCEA linked to the ecd of the CD40 ligand (CD40L). Oral administration of this plasmid DNA vaccine carried by an attenuated strain of Salmonella typhimurium resulted in effective tumor-protective immunity against hCEA-positive mouse colon cancer cells. The induction of immunity in these animals was shown to involve the activation of naïve T cells and dendritic cells (DCs). This vaccine was shown to be capable of activating an immune response against hCEA in animals that were anergic to this antigen and to be 100% effective in the prophylactic setting, but this response required the use of a second treatment, IL-2, which was antibody-targeted to T cells.To administer the tumor-associated antigen (TAA)͞CD40L vaccine in a way that could affect T cells in secondary lymphoid tissue in areas of the body other than the gastrointestinal tract, and to create a therapy that does not require the antibody-targeted IL-2, we constructed replication-incompetent adenoviral vectors encoding chimeric TAA͞ecdCD40L transcription units. These transcription units encode either the human papillomavirus (HPV) E7 foreign tumor antigen or the human MUC-1 (hMUC-1) selfantigen fused to the 209-aa ecd of the CD40L. Thi...

Dendritic cells transduced with an adenovirus vector encoding interleukin-12 are a potent vaccine for invasive pulmonary aspergillosis

“…50 It has been further demonstrated that genetically modified DCs can be successfully applied in tumor immunotherapy and control of some infection. 20,24,46,51,52 Consistent with previous studies, 22,24 in our study, transfection of DCs with AdmIL-12 did not affect their morphology and ability to phagocytose canidia. Most face molecule expression except CD86, which did not change, suggesting the gene modification has little effect on DCs maturation.…”

The Shiga toxin B‐subunit targets antigen in vivo to dendritic cells and elicits anti‐tumor immunity

“…These apparently contradictory results regarding the ability of STxB to induce DC maturation may be explained by the different doses of STxB used, the different subpopulations of DC analyzed or the culture conditions used to generate the bone marrow DC. On the basis of preclinical studies, strategies combining the ability to target and activate DC are considered to be the most efficient to prime CTL responses in mice [46][47][48][49][50][51]. 53], subsequent data showed that CD8a -DC can also channel exogenous antigen into the MHC class I pathway [54,55].…”

The rationale for prophylactic cancer vaccines and need for a paradigm shift

“…57 Another CD40L directed vaccine vector has demonstrated efficacy in an animal model transgenic for the human tumor antigen MUC-1. 58 This tumor antigen is an epithelial mucin glycoprotein that is overexpressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon and ovary. An adenoviral vector vaccine was constructed encoding a fusion protein containing an amino-terminal tumorassociated antigen fragment fused to the CD40L.…”

“…This vector design may therefore be of use in the development of immunoprohylaxis for the many carcinomas in which the hMUC-1 antigen is overexpressed. 58 …”