Liver metastases, which arise from different kinds of tumors, including colorectal cancer and melanoma, remain an unmet clinical need, as they poorly respond to current pharmacological strategies aimed at activating the endogenous anti-cancer immune response. This is because the liver is an immunosuppressive organ per se and liver metastases are able to recruit immunosuppressive cells, which inhibit anti-tumor T cell-mediated response.

To tackle intrinsic immunosuppression and enhance endogenous anti-tumor immune response, the team led by Doctor Mario Leonardo Squadrito, Group Leader in the Vector Engineering and In vivo Tumor Targeting Unit at the San Raffaele Telethon Institute for Gene Therapy , has leveraged gene therapy to arm liver and tumor macrophages and unleash adaptive immunity in mouse models of colorectal and melanoma liver metastases. The study has just been published in Nature Communications.

The Study

The authors have used a previously developed lentiviral vector platform to drive the expression of tumor-associated antigens concurrently with the expression of interferon alpha (IFNα) and interleukin 12 (IL-12) specifically in liver and tumor-associated macrophages in mouse models of liver metastases. A well-tolerated single intravenous injection of lentiviral vectors was employed to arm macrophages against the tumor and promote extensive reprogramming of the tumor microenvironment, including expansion and rejuvenation of tumor-specific cytotoxic T cells. The combined delivery of tumor-associated antigens and immune-activating cytokines was instrumental to enhance T cell-mediated adaptive immune response and prevent tumor growth. “Co-expression of IL-12 and IFNα with tumor-associated antigens is crucial to boost anti-tumor immunity, as compared to the expression of cytokines alone.”, explains Doctor Marco Notaro, first-author of the study.

Future perspectives

The lentiviral vector developed by the authors is a versatile platform that can be equipped with different kinds of tumor-associated antigens as well as immune-activating cytokines to prevent tumor growth by boosting endogenous immune response.

“With this study, we provide the foundation for generating a new class of liver-directed cancer vaccines that unleash endogenous anti-tumor immunity, which in turn inhibits tumor growth,” adds Doctor Squadrito. “In the future, this strategy based on cancer vaccination could help to overcome problems associated with current immunotherapies that use TCR-redirected T cells or CAR-T cells, which require ex vivo expansion and manipulation of patients’ derived T cells”, concludes Doctor Notaro.