Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand

Abstract

Bystander immune activation by chemotherapy has recently gained extensive interest and provided support for the clinical use of chemotherapeutic agents in combination with immune enhancers. The CD40 ligand (CD40L; CD154) is a potent regulator of the anti-tumor immune response and recombinant adenovirus (RAd)-mediated CD40L gene therapy has been effective in various cancer models and in man. In this study we have assessed the combined effect of local RAd-CD40L and 5-fluorouracil (5-FU) administration on a syngeneic MB49 mouse bladder tumor model. Whereas MB49 cells implanted into immunocompetent mice responded poorly to RAd-CD40L or 5-FU alone, administration of both agents dramatically decreased tumor growth, increased survival of the mice and induced systemic MB49-specific immunity. This combination treatment was ineffective in athymic nude mice, highlighting an important role for T cell mediated anti-tumor immunity for full efficacy. 5-FU up-regulated the expression of Fas and immunogenic cell death markers in MB49 cells and cytotoxic T lymphocytes from mice receiving RAd-CD40L immunotherapy efficiently lysed 5-FU treated MB49 cells in a Fas ligand-dependent manner. Furthermore, local RAd-CD40L and 5-FU administration induced a shift of myeloid-derived suppressor cell phenotype into a less suppressive population. Collectively, these data suggest that RAd-CD40L gene therapy is a promising adjuvant treatment to 5-FU for the management of bladder cancer.

IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-β, Collagen Type I, and PD-L1/PD-1

“…We previously demonstrated that immunostimulatory gene therapy using viruses transferring CD40L (AdCD40L) is a potent stimulator of the tumor microenvironment because of its capacity to activate DCs and tilt M2 to M1 macrophages. AdCD40L showed efficacy in mouse, dog, and human (14)(15)(16)(17). In the current paper, we explored the possibility of combining CD40L-based immune activation with IL-6 pathway blockade using virus-mediated gene therapy.…”

Consensus guidelines for the detection of immunogenic cell death

“…These maneuvers include the administration of cardiac glycosides, which are particularly powerful in this respect as they promote per se all major manifestations of ICD (see below), [95][96][97] or zoledronic acid (a bisphosphonate currently approved to treat osteoporosis and to prevent skeletal fractures in cancer patients with bone metastases), 98,99 as well as the provision of co-stimulatory signals via CD40. 100 This said, it should be kept in mind that the capacity of a given agent to cause ICD or exacerbate the immunogenicity of apoptosis cannot be predicted yet from its structural or chemical properties, since molecules as similar to each other as oxaliplatin and cisplatin do not share this functional profile. 39,40 The notion that apoptotic cancer cells do not always go undetected by the immune system has profound clinical repercussions.…”

Combination of calcineurin B subunit (CnB) and 5‑fluorouracil reverses 5‑fluorouracil‑induced immunosuppressive effect and enhances the antitumor activity in hepatocellular carcinoma

“…Recent data suggest that combination therapy not only significantly improves the quality of life of cancer patients (39) but might also improve their responses potentially their survival (47). Indeed, the clinical experience accumulated over the last 30 years of cancer management suggests that combina tions of different agents offer the best possible therapeutic efficacies (10,48). In our experiment, the reduced side effects of combination therapy were evaluated by analyzing the body weights, immune organs indices, peripheral blood platelet and WBC cell numbers, and the pathologies of the livers of the mice.…”