Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments

Abstract

An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I IFN has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1,000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon (AFN)-targeting Clec9Aþ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AFNs provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker. Significance: Targeted type I interferon elicits powerful antitumor efficacy, similar to wild-type IFN, but without any toxic side effects. Cancer Res; 78(2); 463-74. Ó2017 AACR.

Safe eradication of large established tumors using neovasculature‐targeted tumor necrosis factor‐based therapies

“…Quite similar to wtTNF, mCD13‐AFR induced expression of both ICAM‐1 and E‐selectin and repression of VEGF‐R2 at 4 h after injection. Since tumor‐bearing mice tend to be sensitized toward TNF toxicity (Cauwels et al , 2018b), we next tested mCD13‐AFR in the B16Bl6 melanoma model. In stark contrast to wt TNF, daily treatment for 10 consecutive days with a therapeutic dose of mCD13‐AFR caused no significant weight loss or other apparent toxicity, confirming its safety (Fig E).…”

“…It is therefore no surprise that TNF can synergize with immunotherapies such as IL‐2 (Schwager et al , ; Danielli et al , ,b; De Luca et al , ) or adoptive T‐cell transfer (Johansson et al , ). We have previously reported that low‐dose TNF therapy potentiated DC‐targeted AFN therapy (Cauwels et al , 2018b). Here, we show the remarkable synergy of vasculature‐targeted AFR therapy with mCD8‐AFN, targeting cytotoxic T cells (and the cDC1 subset of DCs), leading to profound B16Bl6 tumor elimination.…”

“…mCD8‐AFN and mClec9a‐AFN were generated and produced in E. coli as previously described (Cauwels et al , 2018b).…”

“…Consequently, AcTakines are inactive on their way to the target, thereby eliminating the unfavorable side and sink effects, but regain full activity on the targeted cells by local avidity‐driven receptor binding (Garcin et al , ). We have previously reported the remarkable efficacy of a dendritic cell‐targeted type I interferon AcTakine (AcTaferon, AFN) in multiple tumor models, without side‐effects (Cauwels et al , ,b). In this study, we now demonstrate the efficacy of tumor vasculature‐targeted TNF and IFN‐γ AcTakines (resp.…”

Towards superior dendritic-cell vaccines for cancer therapy

“…Another approach for DC subset-specific targeting employs vaccination with nanoparticles (encapsulating TAAs and TLR ligands) conjugated with the above-mentioned antibodies to avoid damaging systemic inflammation. This nanoparticle-based approach can potentially also be used to deliver cytokines, short or long peptides, total protein or RNA molecules to the target cells 24 .…”