| Abstract |
160 million women develop Breast Cancer (BC) annually with subsequent 500,000 deaths, and therefore it is the second most common cause of cancer related deaths in women. Improved treatments together with earlier diagnosis made the disease more manageable, however 30 –40% of patients will eventually develop metastasis. Metastasis prognosis remains poor, and new therapies effective against advanced and disseminated breast cancer are needed.
Bone is the third most common site for metastatic cancers, after lung and liver. Understanding the molecular pathways promoting bone metastasis may offer new therapeutic targets. Silencing of interferon-α (IFNα) signalling was recently reported as one of the breast cancer bone metastasis hallmarks. Reversing this, may inhibit bone metastasis formation and progression. IFNα is a potent immune stimulator and anti-tumoural molecule, however, its clinical use is limited by the systemic toxicity associated with its therapeutic doses. Therefore, novel therapeutic strategies are essential for the tumour target delivery of IFNα.
Our lab together with Prof Luigi Naldini (TIGET, Milan, Italy) have developed a novel platform for the target delivery of bio-therapeutic molecules to tumour tissues or metastatic organs. This strategy is based on autologous transplantation of gene-modified haematopoietic stem/progenitor cells (HS/PC) expressing the IFNα gene under the control of a cell-specific promoter: the Tie2 promoter. Transplanted HS/PCs then differentiate into all haematopoietic lineages including a subset of tumour-infiltrating monocytes (Tie2-expressing monocytes, TEMs), which specifically upregulate Tie2 after homing to tumour tissues. They previously demonstrated its ability to inhibit primary tumours and lung metastasis in a mouse model of Luminal B breast cancer. They also developed the human delivery platform and showed inhibition of human primary TNBC in a humanised preclinical model. Of note, tumour targeted delivery of IFNα had a positive toxicity profile unlike its systemic administration.
Here, we show that this IFNα-delivery strategy was also able to inhibit TNBC lung and bone metastasis in an immunocompetent preclinical murine model and in a humanised mouse model. Moreover, we tested its ability to improve the outcome of immune checkpoint modulators, or cancer vaccination. As immune checkpoint modulators, we used a new combination currently under investigation in our laboratory that involves anti-PD-1 and anti-41BB antibodies. As a cancer vaccination strategy, we used a novel platform developed in our laboratory for the in vivo delivery of relevant antigen formulations to Clec9A+ dendritic cells and based on tailorable oil-in-water nanoemulsion (Clec9A-TNE). Our results show that this IFNα delivery strategy was able to improve the outcome of cancer vaccination but did not synergies with anti-PD1 and 41-BB.
Finally, thinking about a possible clinical translation, we explored the use of adoptively transferred Tie2-IFNα mature monocytes for the tumour targeted delivery of IFNα in combination with low doses of chemotherapy (Doxorubicin) and showed a significant improvement in the survival of mice treated with this novel combination therapy.
Overall, our data support the clinical translation of our gene- and cell-based therapy for the tumour targeted delivery of IFNα, which has a good safety profile and can enhance therapeutic efficacy when given in combination with best-matching therapies. |
| Keywords |
breast cancer, interferon, TEMs, bone metastasis, immune checkpoint, lentivirus, vaccination, PADRE, TNEs |
