Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1

Abstract

In a cancer gene therapy model recombinant adenoviruses challenge with wild-type tumor but not from challenges with expressing the herpes simplex virus thymidine kinase an unrelated syngeneic tumor cell line. Since cytotoxic T (HSVtk) gene were injected into tumors in situ, either alone lymphocyte responses in this tumor model were weak, we or in combination with adenoviruses (Avs) engineered to analyzed cytokine secretion from spleen cells of treated express IL-2, IL-6 or the costimulatory molecule B7-1.animals. The best correlate of antitumor immunity in this HSVtk phosphorylates the prodrug ganciclovir, thus conmodel was enhanced secretion of GM-CSF, while verting it into an antimetabolite which kills not only HSVtk secretion of IL-2, IL-6 and IFN␥ was also frequently expressing cells, but also by the 'bystander effect', neighincreased but not as consistently. The enhanced IFN␥ boring untransduced tumor cells. The tumors regressed in secretion associated with unchanged IL-4 secretion sug-80% of mice upon AvTK/ganciclovir treatment; combigests that AvTK treatment results in a predominantly Th1-nations with AvIL-2, AvIL-6, or AvB7-1 did not improve mediated antitumor immune response. these results. Cured mice were protected from further

Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model

“…9,10 More recent studies have further demonstrated that HSVtk + GCV therapy can lead to the induction of a Th1 immune response that may play a role in the observed antitumor immunity. 11,12 Therefore, to extend our previous work towards a more direct immunomodulatory gene therapy approach, we considered in situ adenovirus-mediated IL-12 gene transduction as a therapy for prostate cancer.…”

Potentiation of antitumor immunity by antibody-directed enzyme prodrug therapy

“…Treatment of tk-or CD-transduced tumors with GCV or 5-FC in many instances produced similar antitumor immunity as immunization with radiation-or drug-treated tumor cells, 39,40 only weak or no CTL activity after prodrug treatment of tumors 37,41,42 and incomplete 29,39 or no 43,44 protective immunity. ADEPT, in contrast, generated long-lasting systemic antitumor immunity that could not be generated by immunization of radiation-treated tumor cells even with addition of immunoenzyme (Fig.…”

Gene therapy of hepatocarcinoma: a long way from the concept to the therapeutical impact

“…In some immunocompetent animal models of HCC, a distant bystander effect relying on the activation of the immune system has been described, which synergizes with the direct elimination of tumor cells. [114][115][116][117] HSV-TK/GCV treatment has been extensively experienced in vitro and in animal models either with tumors obtained following injection of HCC lines or chemically induced HCC as shown in DEN-induced HCC in the rat model. 104,118 In this last model, using adenoviral vectors to transfer the HSV-TK gene, we have shown that a unique intratumoral injection of the viral vector with daily administration of GCV allows strong reductions of large-size tumors.…”