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This article discusses the development of a lentiviral vector-based gene therapy platform for the treatment of liver metastases (LMS). Liver metastases commonly arise from gastrointestinal tumors and are difficult to treat due to the immunosuppressive environment of the liver. The lentiviral vector delivers interferon-alpha (IFNα) to liver macrophages, which activates the immune system and reduces the growth of LMS. The study also found that combining gene-based IFNα delivery with monoclonal antibodies blocking CTLA-4 resulted in a strong therapeutic response. The use of lentiviral vectors in gene therapy has shown promise in various clinical applications and has the potential to be used in the treatment of LMS. [Extracted from the article]

Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need. [Display omitted] • IFNα from in vivo LV-engineered liver macrophages curbs liver metastasis growth • IFNα activates antigen presentation and CD8+ T cell effector function • Resistance to IFNα is associated with Eomes CD4+ T cells, IL-10 signaling, and CTLA-4 • IFNα combined with anti-CTLA-4 bypasses resistance attaining complete response In this study, Kerzel et al. describe a lentiviral vector platform to selectively engineer liver macrophages to deliver IFNα to liver metastases from within the tissue achieving therapeutic efficacy. Simultaneous combination with anti-CTLA-4 bypassed resistance mechanisms and expanded tumor-reactive T cells, attaining complete response in most mice. [ABSTRACT FROM AUTHOR]