Our Science

Cancer Immunotherapy

Our gene therapy science to treat cancer

We develop a gene transfer strategy into autologous hematopoietic stem/progenitor cells (HSPCs) to target interferon-α expression to tumor-infiltrating monocytes/macrophages. An HIV-derived and genetically disabled viral vector - Lentivirus - delivers the gene into the HSPCs. Interferon is a protein usually produced by the body in response to infections that also exhibits a powerful anti-tumor activity.
However, the clinical use of interferon as a drug has been limited by its high toxicity. Thanks to our innovative therapy, using a combination of transcriptional and microRNA-mediated control, tumor-infiltrating monocytes/macrophages become capable to selectively express interferon limited to the tumor area, thus reducing its toxicity.
Based on these mechanisms, a population of tumor-infiltrating monocytes/macrophages, TIE2-expressing monocytes (TEMs), are armed with a specific drug.

The immunosuppressive tumor microenvironment represents a major hurdle to cancer therapy. We developed a gene transfer strategy into hematopoietic stem cells (HSCs) to target transgene expression to tumor-infiltrating monocytes/macrophages. Using a combination of transcriptional and microRNA-mediated control, we achieved selective expression of an interferon-α (IFN-α) transgene in differentiated monocytes of human hematochimeric mice. We show that IFN-α transgene expression does not impair engraftment and long-term multilineage repopulation of NSG (NOD/LtSz-scidIL2Rγnull) mice by transplanted human HSCs. By providing a source of human cytokines in the mice, we improved the functional reconstitution of human myeloid, natural killer, and T cell lineages, and achieved enhanced immune-mediated clearance of transplanted human breast tumors when hematopoiesis was engineered for tumor-targeted IFN-α expression.
By applying our strategy to mouse breast cancer models, we achieved inhibition of tumor progression and experimental metastases in an autologous setting, likely through enhanced generation of effector T cells and their recruitment to the neoplastic tissues. By forcing IFN-α expression in tumor-infiltrating macrophages, we blunted their innate protumoral activity and reprogrammed the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. Overall, our studies validate the feasibility, safety, and therapeutic potential of a new cancer gene therapy strategy, and open the way to test this approach as adjuvant therapy in advanced breast cancer patients.

Copyright © 2014,
American Association for the Advancement of Science

Science Translational Medicine 01 Jan 2014:
Vol. 6, Issue 217, pp. 217ra3
DOI: 10.1126/scitranslmed.3006353

Luigi Naldini

Modified stem cells for therapeutics applications

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