Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours

Abstract

Checkpoint inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin (IL)-12 is a powerful cytokine that activates the innate and adaptive arms of the immune system, yet its administration has been associated with immune-related adverse events. Here, we show that the intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive murine tumours accumulates in the tumour stroma, owing to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoral levels of interferon-, markedly reduced its systemic levels as well as organ damage, and led to superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanoma, induced antigen-specific immunological memory, and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.

Localized Interleukin-12 for Cancer Immunotherapy

“…Systemic (i.v.) administration of this CBD-IL12 was found to accumulate in EMT6 mammary carcinomas at significantly higher levels and induce higher rates of complete tumor regression against 1-week old B16F10 and EMT6 tumors compared to IL-12 ( 104 ). Inclusion of the CBD resulted in a 5–6-fold decrease in plasma half-life despite the larger size of CBD-IL12.…”

“…injection were surprisingly similar although typical sites of collagen targeted drugs, e.g., bone and skin, were not examined. Most importantly, although elevated liver enzymes were observed, levels following CBD-IL12 at an impressive dose of 50μg/mouse were similar to 10μg/mouse of IL-12 ( 104 ).…”

“…Another collagen-binding immunocytokine comprised of the A3 CBD of von Willebrand Factor fused to both subunits of IL-12 was also recently developed ( 104 ). Systemic (i.v.)…”

Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

“…We 22 and others previously found that IL-12 can improve cancer immune elimination via enhanced CD8 + T cell proliferation, 24 cytotoxicity, 17, 25 survival, 17 and T cell receptor (TCR) signaling. 26,27 As clinically approved T cell engager therapies are thought to act primarily on a subset of CD8 + T cells, 28,29 we posited that IL-12 may improve the lytic activity of blinatumomab which bi-specifically targets T cell CD3 and leukemic B cell CD19.…”

Human Vaccines & Immunotherapeutics: news

“…Interleukin 12 (IL-12) increased intratumoral inflammation and improved checkpoint blockade immunotherapy in a mouse model of melanoma. 5 The recombinant cytokine was fused to a collagen-binding domain, which targets the exposed collagen in the leaky vasculature in the tumor. The combination with a checkpoint inhibitor eradicated large tumors in the experimental animals.…”