Local gene delivery of tumor necrosis factor alpha can impact primary tumor growth and metastases through a host-mediated response

Abstract

TNFerade is a replication incompetent adenovector designed to express human TNFalpha under control of the Egr-1 radiation and chemotherapy enhanced promoter, and is currently in Phase II/III clinical testing. Data from Phase I clinical testing of TNFerade in a limited set of melanoma patients suggested the potential to impact distal metastases following intratumoral injections of TNFerade. These clinical observations and the multiple potential mechanisms of TNFerade led us to hypothesize local treatment with TNFerade + radiation may impact metastatic disease. We explored this hypothesis in preclinical models using the spontaneously metastatic, syngeneic B16F10 murine melanoma model. Established subcutaneous B16F10 tumors were treated with intratumoral injections of TNFerade and localized 2 Gy fractionated radiation therapy, modeling the clinical treatment regimen. Following 10-14 days of treatment, mice were evaluated for metastases development in the iliac and axillary lymph nodes. Comparisons of metastatic burden to control groups indicated TNFerade +/- radiation suppressed the formation of metastases in the lymph nodes. Additional experiments in TNF receptor knockout mice, where the only possible effects are on tumor cells containing the TNFalpha receptor, indicate TNFerade's local and distal activities are critically dependent on a host-mediated response. These data provide direct preclinical evidence local therapy of a solid tumor with TNFerade can also reduce metastatic disease, in addition to effects on the treated lesion. Furthermore, our finding of a host dependant response(s) for TNFerade at both the treated tumor and on lymph node metastases suggest the potential for broad activity independent of tumor histology.

Intratumoral delivery of CD154 homolog (Ad-ISF35) induces tumor regression: analysis of vector biodistribution, persistence and gene expression

“…15,16 However, this procedure requires leukapheresis of tumor cells, which are not always available and ex vivo manipulation of the cells at specialized facilities. Several groups have used intratumoral administration of recombinant adenoviral vectors as a promising strategy for effective local gene transfer, 20–24 avoiding the hepatotoxicity and anaphylactic reactions induced by systemic intravenous administration. 25–29 Therefore, we evaluated the administration of Ad-ISF35 by intratumoral direct injection, which allows us to expand potentially the clinical application of Ad-ISF35 in lymphomas and solid tumors.…”

Combination of human tumor necrosis factor-alpha (hTNF-α) gene delivery with gemcitabine is effective in models of pancreatic cancer

“…6,[17][18][19][20] In multiple cancer models tested to date including, esophageal, head and neck, melanoma, colon adenocarcinomas and gliomas, radiation is able to induce and regulate the expression of hTNF-a protein from the Egr-1 promoter in a dose-related manner. Moreover, by directing the radiation at the tumor and delivery of AdEgr.TNF.11D directly into the tumor, hTNF-a production is selectively limited to the tumor and the potent cytotoxic effects of hTNF-a on normal tissues are substantially reduced.…”

“…The hTNF-a has showed necrosis activity in a wide variety of cancer cells, selective apoptotic activity on tumor vasculature, and may have distal effects that suppress metastases. 5,6 Induction of apoptosis is the likely primary mechanism of direct cytotoxicity by hTNF-a and is probably mediated through the TNFRI receptor present on most cell types. 5 The hTNF-a also induces apoptosis in tumorassociated endothelial cells and sensitizes the tumor cells to radiation 7 and chemotherapeutic drug.…”

Translation of the radio- and chemo-inducible TNFerade vector to the treatment of human cancers

“…Finally, the results could be due to the effects of TNF-a on induction of an immune response against the tumor cells. 63 Effects of TNF-a on antitumor immunity TNF-a has been linked to antitumor immunity as a cytotoxic effector that is secreted by macrophages and natural killer cells. 64,65 TNF-a also interacts with other cytokines in the maturation of dendritic cells, is essential for modulating thresholds for activation and tolerance of CD8 þ cells and increases major histocompatibility complex (MHC) class I expression.…”