Research ArticleCancer

Targeted antibody and cytokine cancer immunotherapies through collagen affinity

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Science Translational Medicine  10 Apr 2019:
Vol. 11, Issue 487, eaau3259
DOI: 10.1126/scitranslmed.aau3259

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Conjugated bliss

Immunotherapies for cancer are becoming increasingly common due to their impressive ability to activate the patients’ own immune system to fight tumors. However, systemic approaches to immune system activation are not risk free, and immunotherapies are often associated with corresponding immune side effects, which can be severe. To address this problem, Ishihara et al. conjugated immune checkpoint inhibitors and the cytokine interleukin-2 to the collagen-binding domain from a blood protein, allowing them to bind to tumor stroma and exert their effects locally. The researchers tested this approach in multiple mouse models, demonstrating improved efficacy and safety compared to the unconjugated molecules.

Abstract

Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti–cytotoxic T lymphocyte antigen 4 antibody (αCTLA4) + anti–programmed death ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4 + αPD-L1 combination therapy and IL-2, for example, eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD–IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD–IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast cancer model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically administered tumor drugs with high translational promise.

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