The establishment of an immunosuppressive microenvironment is one of the hallmarks of cancer and the major impediment to the successful application of cancer immunotherapy. By exploiting the tumor homing ability of a subpopulation of monocytes we turned them into an efficient vehicle for the tumor-targeted delivery of a potent immune-stimulatory molecule: interferon-alphaIFNα. We are now combining the ability of IFNα to reverse the immunosuppressive tumor microenvironment with established and new cancer immunotherapies for the treatment of advanced breast cancer, including disseminated lung and bone metastasis.
We identified and characterized a specific subpopulation of pro-tumoral macrophages characterized by the expression of the Angiopoietin receptor TIE2 (TEMs: TIE2-expressing monocytes/macrophages) and endowed with pro-angiogenic and immunosuppressive activities. As a strategy aimed at reversing the immunosuppressive microenvironment, we exploited the tumor homing ability and selective expression of the TIE2 receptor to turn TEMs into IFNα delivery vehicles by engineering hematopoietic stem cells (HSCs) to express an IFNα transgene under the control of the Tie2 promoter. To progress this strategy to clinical application we recently developed a humanized vector expressing a human IFNα gene, and have studied the feasibility and safety of engineering human HSCs for its expression in their TEM progeny. Moreover, to demonstrate the efficacy of our human IFNα delivery platform, we challenged human hematochimeric mice with a human breast cancer cell line.
Type I interferons (IFNs) are pleiotropic cytokines involved in innate and adaptive immunity that have been shown to promote anti-tumor immune responses. The broad anti-tumor biological activities of type I IFNs have provided the rationale for testing administration of exogenous IFNα as an anti-cancer treatment, which has proven effective against several solid and hematological malignancies. However, clinical use of IFNα has since declined because of the substantial toxicity associated with systemic administration and the limited efficacy at the maximal tolerated doses, thus calling for safer and more effective delivery strategies.
Our cell- and gene-based IFNα delivery strategy strongly inhibited primary breast cancer tumors and breast cancer lung metastasis in mouse and human hematochimeric models by promoting the recruitment and activation of both innate and adaptive immune cells with no evident signs of toxicity. Moreover, our studies validated the feasibility, safety and therapeutic potential of a new HSC-based gene therapy strategy to treat established tumors, and could, therefore, revive interest in testing high-dose chemotherapy followed by autologous HSC transplantation in advanced breast cancer patients.
Importantly, we think that the multiple activities of type I IFNs in the complex network of cell interactions that lead to activation and deployment of immune responses may represent a valid strategy to promote and improve the outcome of cancer immunotherapy for the treatment of advanced breast cancer including lung and bone metastasis. Preliminary data on new therapeutic strategies combining TEM-mediated delivery of IFNα with monoclonal antibodies against inhibitory checkpoint molecules such as PD1 and CTLA4, will be presented. |
