Enhanced immune response to the melanoma antigen gp100 using recombinant adenovirus-transduced dendritic cells.

Glycoprotein 100 (gp100) is one of a series of well-characterized human melanoma-associated antigens expressed by most melanoma cells. Immunization of C57BL/6 mice with an adenovirus (Ad) vector encoding human gp100 (Adhgp100) has been shown to induce limited protective immunity against challenge with murine melanoma B16 cells. In the current study we determined whether gp100-specific immunity can be enhanced using bone-marrow-derived dendritic cells (DCs) transduced with Adhgp100 ex vivo. Subcutaneous injection of Adhgp100-infected DCs resulted in potent T-cell-mediated protective immunity and a greater than 80% reduction of established tumors when administered to B16 tumor-bearing hosts. Compared to direct injection of Adhgp100 vector alone, immunization with Adhgp100-infected DCs induced markedly greater antitumor activity. In vitro CTL analysis demonstrated that DC-Adhgp100 immunization activated both CD4(+) and CD8(+) CTLs, while no lytic activity was generated by vaccination with Adhgp100 alone. In vivo depletion of CD4(+) T cells, but not CD8(+) T cells, completely abrogated CTL activity, suggesting that Adhgp100-transduced DCs result in activation of both CD4(+) and CD8(+) CTLs via a CD4(+)-dependent mechanism. We speculate that this improved efficacy of Adhgp100-transduced DCs compared to direct immunization with Adhgp100 may be the result of direct DC-mediated CD4(+) T cell activation. These results emphasize the importance of CD4(+) T cells in the development of therapeutic antigen-specific cancer vaccines.

Wan Y ，Emtage P ，Zhu Q ，Foley R ，Pilon A ，Roberts B ，Gauldie J ... -  《CELLULAR IMMUNOLOGY》

Dendritic cell-based genetic immunization in mice with a recombinant adenovirus encoding murine TRP2 induces effective anti-melanoma immunity.

Tüting T ，Steitz J ，Brück J ，Gambotto A ，Steinbrink K ，DeLeo AB ，Robbins P ，Knop J ，Enk AH ... -  《JOURNAL OF GENE MEDICINE》

Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens.

:Dendritic cells (DCs) are professional Ag-presenting cells that are being considered as potential immunotherapeutic agents to promote host immune responses against tumor Ags. In this study, recombinant adenovirus (Ad) vectors encoding melanoma-associated Ags were used to transduce murine DCs, which were then tested for their ability to activate CTL and induce protective immunity against B16 melanoma tumor cells. Immunization of C57BL/6 mice with DCs transduced with Ad vector encoding the hugp100 melanoma Ag (Ad2/hugp100) elicited the development of gp100-specific CTLs capable of lysing syngeneic fibroblasts transduced with Ad2/hugp100, as well as B16 cells expressing endogenous murine gp100. The induction of gp100-specific CTLs was associated with long term protection against lethal s.c. challenge with B16 cells. It was also possible to induce effective immunity against a murine melanoma self Ag, tyrosinase-related protein-2, using DCs transduced with Ad vector encoding the Ag. The level of antitumor protection achieved was dependent on the dose of DCs and required CD4+ T cell activity. Importantly, immunization with Ad vector-transduced DCs was not impaired in mice that had been preimmunized against Ad to mimic the immune status of the general human population. Finally, DC-based immunization also afforded partial protection against established B16 tumor cells, and the inhibition of tumor growth was improved by simultaneous immunization against two melanoma-associated Ags as opposed to either one alone. Taken together, these results support the concept of cancer immunotherapy using DCs transduced with Ad vectors encoding tumor-associated Ags.

Kaplan JM ，Yu Q ，Piraino ST ，Pennington SE ，Shankara S ，Woodworth LA ，Roberts BL ... -  《JOURNAL OF IMMUNOLOGY》

Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12.

Okada N ，Iiyama S ，Okada Y ，Mizuguchi H ，Hayakawa T ，Nakagawa S ，Mayumi T ，Fujita T ，Yamamoto A ... -  《CANCER GENE THERAPY》

The boosting effect of co-transduction with cytokine genes on cancer vaccine therapy using genetically modified dendritic cells expressing tumor-associated antigen.

Ojima T ，Iwahashi M ，Nakamura M ，Matsuda K ，Naka T ，Nakamori M ，Ueda K ，Ishida K ，Yamaue H ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》