2015 Mentored Investigator Grant Recipient — Alfredo Perales-Puchalt, MD
Ovarian cancer is one of the most deadly tumors, killing ~15,000 women each year in the US. Despite advances in its treatment, survival of women with this disease has not improved in the last 40 years. Our group has helped to demonstrate that ovarian cancer can be fought by the immune system.
In recent years, the use of the CAR therapy (a type of immune system therapy where immune cells are armed with a protein that recognizes selected proteins in the cancer cell) has shown impressive cures for patients with blood cancers. However, its use in solid tumors has been difficult because there are few proteins that can be targeted in cancer cells that are not present in healthy cells; in that case, the immune cells would also attack the healthy cells, being toxic for the patient.
The follicle-stimulating hormone receptor (FSHR) is only expressed in women in the ovaries and, importantly, in 50-70% of ovarian cancers. Given that removing the ovaries is a standard procedure in the treatment of ovarian cancer, targeting the FSHR should not cause damage to healthy cells. An advantage of using that target is that there is a hormone that only recognizes that protein and it is naturally in the body. We will use that hormone as part of the protein for arming the immune system and recognize the FSHR. In the past, instead of this, they have used parts of antibodies, which are not as selective. As it is naturally human, unlike the antibodies that are raised in other animals, it will not have problems of immune reactions against it.
Our objective is to develop a new therapeutic weapon that can be used in clinical trials using patients’ own immune systems to fight ovarian cancer and prevent its recurrence. For that purpose we have developed a CAR that includes the hormone and other parts of the CAR protein that successfully worked for curing blood cancers. We want to prove that our new CAR therapy will be able to kill FSHR expressing tumor cells and increase survival in clinically relevant ovarian cancer models without damage to healthy organs, so that this new therapy can be safely used in ovarian cancer patients. For that we will:
1. Study the effectiveness vs. toxicity of our CAR in mouse ovarian cancer models. We will test if it will kill tumor cells that express FSHR but will be safe for the healthy cells. 2. Define the effectiveness of our CAR against human ovarian cancers implanted in mice. By using the same patients’ tumors and immune cells, we will simulate a clinical trial with ovarian cancer of real patients.
This grant was made possible in part by a generous donation from Ovarian Cycle Washington, DC.
Dr. Perales-Puchalt is Postdoctoral fellow of the Tumor Microenvironment and Metastasis Program at the Wistar Institute, in the laboratory of Dr. Conejo-Garcia. He graduated as M.D. from Universitat de Valencia, Spain, and completed a residency in Obstetrics and Gynecology at the La Fe Hospital, in Valencia, Spain and a Master in Human Reproduction in Universitat de Valencia, Spain. He graduated with a Bachelor in Statistics in Health Sciences and a Master in Methodology in Research in Health Sciences from Universitat Autonoma de Barcelona, Spain. After residency he got a research fellow position in Reproductive Medicine at the Pennsylvania State University College of Medicine for doing clinical investigation. Currently, at the Wistar Institute, his focus is in both basic and translational research to advance the understanding of tumor immunology and to develop novel immunotherapies for ovarian cancer for future implementation in clinical trials. He graduated with an extraordinary award from medical school in 2007, got a residency program award from the Hospital Universitari i Politècnic La Fe in 2012 and was also awarded in 2012 with a research fellowship from Fundación Alonso Martín Escudero.