Perelman School of Medicine at the University of Pennsylvania

Dr. Facciabene Andrea, Radiation Oncology / OBGYN

Dr. Facciabene Andrea, Radiation Oncology / OBGYN

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.

In the labTargeting 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.

Granulosa Ovarian Cancer:

Granulosa cells tumors (GCT) are rare tumor of the ovary as they account for only 3–8% of primary ovarian tumor; with poor prognosis as the tumor-related mortality rate is 40%. The transcription factor Forkhead box L2 “FOXL2” is up-regulated in GCT while it is undetectable in other tissues; moreover a somatic mutation (C134W) of the FOXL2 gene has been consistently identified in adult granulosa cell tumors. We assessed whether FOXL2 represents a potential therapeutic target for GCT immunotherapy by immunizing immunocompetent mice with a DNA plasmid vaccine encoding FoxL2 cDNA, including the mutation (C134W), referred to herein as FoxL2-TT vaccine. FoxL2-TT vaccination of C57BL6 and BALB/c mice breaks the tolerance to FOXL2 protein as demonstrated by reactivity of vaccine-primed T cells against specific FOXL2 epitopes. Vaccination in human HLA-A2 Tg (HHD) transgenic mice results in the induction of HLA-A2-restricted CD8+ T cells against the immune dominant  human FoxL2 peptide. Moreover, Peripheral Blood Mononuclear Cells (PBMCs) from GCT patients showed spontaneous reactivity against immunodominant FOXL2 peptide/s validating FOXL2 as a target for immunotherapy of GCT. Interestingly, Tumor Infiltrating Lymphocytes (TILs) of a GCT patient were successfully expanded in-vitro and tested against patient’s own tumor cells showing reactivity. To our knowledge this is the first evidence of the opportunity to develop both active and passive immunotherapy approaches for GCT.


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