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Adoptive transfer of genetically engineered monocytes for the tumour targeted delivery of IFN-alpha

      The establishment of an immunosuppressive microenvironment is one of the hallmarks of cancer and the major impediment to the successful application of cancer immunotherapy. To re-activate an anti-tumoural response, we have previously developed a strategy which is able to reverse the immunosuppressive tumour microenvironment. Specifically, we turned a pro-tumoural population of macrophages, the TIE2-expressing monocyte/macrophages (TEMs), into cellular vehicles for the tumour targeted delivery of a potent immune-stimulatory molecule: interferon-α (IFNα). This was achieved by exploiting their tumour homing capability and selective expression of the angiopoietin TIE2 receptor. Using lentiviral vectors (LVs), we introduced an IFNα transgene regulated by the enhancer/promoter of the mouse Tie2/Tek gene into transplanted murine hematopoietic stem cells (HSCs), and showed selective activation of IFN-α expression in their TEM progeny recruited to tumours. This cell- and gene-based delivery therapy strongly inhibited primary breast cancer tumours and lung metastasis in mouse and human hematochimeric models with no evidence of toxicity. However, despite clinical evidences for safe and effective HSC gene transfer by LVs in clinical trials, autologous HSC transplantation is not currently used in breast cancer patients. On these grounds, as a clinically applicable alternative to HSC transplantation in the setting of breast cancer, we explored adoptive transfer of autologous genetically engineered monocytes and have preliminary data supporting tumour homing of adoptively transferred monocytes and delivery of IFNα to both primary and metastatic lesions in mouse and humanized models of breast cancer, thus providing a valid strategy for the delivery of anti-tumoural biomolecules to the tumour microenvironment.
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