Pre-clinical and clinical development of leukemia stem cell inhibitors in acute leukemias

In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy.

“Clinical and biological role of adjuvant dendritic cells vaccination in newly glioblastoma patients”

Background. Glioblastoma (GBM) is the most common primary tumor of central nervous system and it has a poor prognosis. Standard first line treatment, which includes surgery followed by adjuvant radio-chemotherapy,produces only modest benefits to survival. The interest for immunotherapy in this field derives from the development of new drugs and effective therapies as immune-check points inhibitors, adoptive T-cell approaches or dendritic cell (DC) based vaccines or a combinations of these. GBM is described as a typical “immune-deserted” cancer exhibiting a number of systemic and environmental immunosuppressive factors. Considering the role of microenvironment, and above all the lower tumor load and depletion of immunosuppressive cells in GBM, our hypothesis is that DC vaccine may induce an immune response. Main aims and study design. The main aim of this project is to study the role of immune system in GBM, including identification of potential prognostic and predictive markers of outcome and response to dendritic cell vaccine. Firstly, we performed a retrospective analysis on blood samples. Then, we analyzed the immuno-component in tissues samples of enrolled patients; and compared that with blood results. Then, the last part of the project is based on a prospective clinical trial on patients enrolled in DC-based vaccination produced at IRST Cell Factory and actually used for patients with melanoma and other tumors. The enrollment is still ongoing. Expected results. The project will i) develop an immune-panel of prognostic and predictive markers to help clinicians to improve the therapeutic strategy for GBM patients; ii) provide preliminary results on the effectiveness of immunotherapy on GBM patients.