Our Research
Identification of new Tumor Antigens:
Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. We previously showed that the RENCA tumor cell line harbors TAMAs which can drive an antitumor immune response. Approximately 30-40% of the vaccinated animals rejected the tumors and in the rest of the animals the tumor grew much slower than the controls but the effects were not complete. We investigated a possible correlation between immune checkpoint up-regulation in our model and we found that PD-L1 mRNA was up-regulated within tumor in comparison with healthy kidney and such level was augmented in cancer from treated mice. This finding suggested a direct correlation between PD-L1 expression, a T-cell response, and tumor escape from the mitochondria vaccine. On the basis of these results, we are currently exploring: a) the addition of PD1/PD-L1 blockade to our approach b) validating the mouse data in humans c) validating the data in other mouse models of cancers.
Targeting the Tumor Vasculature:
Angiogenesis plays a critical role in supporting tumor growth and antiangiogenesis agents blocking vascular endothelial growth factor (VEGF) have shown therapeutic activity in a proportion of patients with common solid tumors but have also revealed the complexity of this field. Therefore, development of therapies that directly target and kill tumor endothelial/stromal cells rather than neutralizing angiogenic factors appears a rational alternate strategy. Tumor endothelial marker 1 (TEM1, also known as endosialin or CD248), is a tumor vascular-specific protein in the human and mouse. TEM1 is expressed by tumor endothelial and tumor endothelial precursor cells (EPC) by pericytes and by tumor associated fibroblasts. We have developed a new DNA vaccine fusing the mouse tem1 cDNA with the minimal domain of the C-fragment of tetanus toxoid (tem1-TT). We vaccinated tumor-bearing immunocompetent mice; immunization reduced tumor vascularity, increased tumor CD3+ T cell infiltration and controlled progression of established tumors in several different mouse models. On these exciting results we are perusing clinical development of the published vaccine and possible combination with radiotherapy.
TEM1 is expressed by tumor endothelial and tumor endothelial precursor cells (EPC) by pericytes and by tumor associated fibroblasts. We have developed a new DNA vaccine fusing the mouse tem1 cDNA with the minimal domain of the C-fragment of tetanus toxoid (tem1-TT). We vaccinated tumor-bearing immunocompetent mice; immunization reduced tumor vascularity, increased tumor CD3+ T cell infiltration and controlled progression of established tumors in several different mouse models. On these exciting results we are perusing clinical development of the published vaccine and possible combination with radiotherapy.
Gut Microbiota and Cancer:
In 400 B.C., Hippocrates first said, “all disease begins in the gut”. The gut microbiota represents the microorganisms including bacteria, fungi and viruses that live in the digestive tracts of humans and other animals. Many diseases that have dramatically increased in incidence over the past few decades such as cancer, obesity, diabetes, atherosclerosis, asthma, and inflammatory bowel disease have both genetic and environmental components. Environmental factors include changes in diet, increased use of antibiotics, increasingly sedentary lifestyle, cesarean births, and vaccinations. Each of these factors is associated with alterations in the gut microbiota. Nowadays, there are mounting evidence that gut microbiota can modulate the patient's response to cancer therapy through immune interactions, xenometabolism and altered community structure. We were the first to demonstrate the impact of gut microbiota on Adoptive Cells and Radiation Therapies. We found that modulation of the gut microbiota trough oral Vancomycin can increase antigen presentation and secretion of IL-12 by Dendritic Cells and in turn the increase level of IL-12 and Tumor Associated Antigen presentation help the antitumor effects of both therapies. We are now investigating the role of the gut microbiota in Chimeric Antigen Receptor therapy.
