Giovanni Grignani, M.D.
Integrated therapies for the treatment of sarcomas
Bone and soft tissue sarcomas (B-STS) are a rare and heterogeneous group of tumors. As of today, a multidisciplinary treatment encompassing complete surgical removal of the tumor +/- chemotherapy and radiotherapy cures roughly 50% of patients. Unfortunately, the most active chemotherapies may eradicate micro-metastatic disease, but do not cure non-resectable disease. Several second- and further-line treatments have been tested showing marginal activity at most. Therefore, innovative therapeutic strategies are urgently needed.
We focused on the identification of key-pathways that can be exploited with innovative therapeutic tools. In osteosarcoma we identified the role of the mTOR pathway as a mechanism of resistance to sorafenib and showed the possibility of hitting this pathway with an innovative target combination therapy with sorafenib and everolimus. In this context we ran and completed a phase II trial. We identified on several B-STS the expression of specific antigens that can elicit a MHC-unrestricted T-cell immune-response. Thereafter, we demonstrated in B-STS patients that we could sort and ex-vivo expand a specific T-cell sub-population endowed with antitumor activity directed against patients’ tumors. After ongoing AIFA protocol approval, a phase I/II trial will be run within the Italian Sarcoma Group.
Conclusions and perspectives:
The achieved results show the importance of dissecting B-STS heterogeneity to identify histotype specific Achilles’ heel. Moreover, we are developing a form of immunotherapy that can be combined with any of the multidisciplinary therapies that are the real backbone of sarcoma treatment. In perspective we look for an even greater integration with the other immunotherapeutic tools directed to reactivating patient anti-tumor response. Secondly, several new compounds with improved selectivity to targets are in development. We have built a successful partnership with several pharmaceutical industries based on clinical trials designed and conducted by our team. On this ground, we will keep on joining international trials of important drugs, as we did with pazopanib, and investigating combination therapies based on our preclinical/translational research activity.