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Penn Ovarian Cancer Research Center Immunotherapy Program
Mission
In its personalized approach to treating cancer, the Ovarian Cancer Research Center (OCRC) focuses its efforts on developing new therapies which boost the body's own ability to fight cancer. The underlying notion is that tumors are different enough from the normal body, such that they can be recognized and attacked as "foreign" by the host's immune system, once the immune defenses are properly educated and activated. This process is known as immunotherapy.
The Center has a unique solid immunotherapy program with the infrastructure necessary to take therapies from bench to bedside. The ovarian cancer trials that are currently being conducted are highly personalized and each aims at "educating" a patient's body to fight her tumors. The immune cells that pick up the tumor unique proteins (antigens) and present them to the immune system are called dendritic cells. These are the sentinels of the immune system. After a dendritic cell picks up tumor antigen, it travels to the lymph nodes (the working stations of the immune system) and activates lymphocytes (the soldiers of the immune system). Lymphocytes exit the lymph nodes and seek the tumor, where they attack and kill tumor cells.
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This process happens naturally in many patients and is associated with longer survival. However, lymphocytes generated spontaneously are too few and arrive "too late". This process can be boosted by tumor vaccines. Immune therapies optimize the function of dendritic cells and lymphocytes.
Vaccine Approaches
At the OCRC we develop tumor vaccines using protein extracted from the whole fresh tumor obtained at the time of surgery. We have developed two distinct and complementary approaches. The first approach uses the patient's tumor to derive vaccines without prior knowledge of which antigens are expressed by the tumor. Although these antigens may not be known, they can still induce a potent immune response, because they can be effectively recognized by the immune system as "foreign" or "non-self". The second approach relies on the unique antigen profile of the patient's tumor. Each patient's tumor expresses unique proteins (antigens) that can be recognized and attacked by the immune system. This type of immunotherapy is highly personalized. Thus, immune therapy can be designed specifically for each patient, maximizing the potential for success.
The purpose of administering tumor vaccines is to boost pre-existing anti-tumor immune response as well as induce an immune response against new tumor antigens or in patients lacking spontaneous immunity.
There are currently two phase I/II clinical trials for patients with recurrent ovarian cancer using different approaches to manufacture personalized vaccine, developed from the patient's tumor:
UPCC 19809: Uses protein (lysate) extracted from the patient's viably frozen tumor. The protein is loaded onto dendritic cells manufactured in the laboratory from the patient's blood cells. This personalized vaccine is administered every two weeks for a total of 5 times. The vaccine is now combined with bevacizumab, a drug commonly used to block angiogenesis (the growth of new blood vessels). Two weeks after the last injection, the patient undergoes a CT scan to assess the tumor burden.
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UPCC 29810: Uses protein (lysate) extracted from the patient's viably frozen tumor. The protein is given intradermally with tiny injections. Patients receive vaccine every two weeks for a total of 5 times. In some patients, vaccine is combined with intravenous Ampligen, to test if this agent will further activate the immune system and increase the effects of the vaccine. Ampligen is given every 2-3 days for three times after every vaccine. Two weeks after the last vaccine injection, the patient undergoes a CT scan to assess the tumor burden.
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Adoptive T cell Therapy Approach
Although cancer vaccines (especially those using whole tumor antigen) are expected to have efficacy, amplifying the vaccine response can be accomplished through the various combinations described above or through adoptive lymphocyte therapy. Adoptive transfer of T cells has emerged as the most powerful approach to date for the treatment of patients with advanced malignancies. This is done by harvesting post-vaccine blood lymphocytes, activating them in culture, and infusing them back to the patient following a short course of high dose (non-myeloablative) chemotherapy.
UPCC 26810: is a phase I trial currently enrolling patients who have completed vaccine studies. During the previous vaccine studies, we collect the patient's blood through a process called apheresis. Vaccine-activated T cells are isolated from the blood and stored viably until the patient is ready to enroll in this study. Once the patient enrolls, she receives three days of chemotherapy followed by infusion of her own activated lymphocytes. This approach is expected to boost the effects of the previous vaccines. Patients have the option of receiving additional maintenance vaccines.
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Tumor Infiltrating Lymphocytes:
A large proportion of patients with ovarian cancer (approximately half) exhibit spontaneously anti-tumor immune response at the time of diagnosis. In these patients, tumor-reactive lymphocytes (T cells) recognizing the tumor can be isolated directly from their tumors at the time of surgery. The T cells are processed, stored and subsequently used for immunotherapy. When the patient is ready for immunotherapy, she receives three days of chemotherapy followed by infusion of her own activated lymphocytes in combination with cytokine therapy. The OCRC will launch this trial in early 2012.
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Genetically Engineered T cell Therapy Approach:
In addition to the above methods, we are preparing to launch a series of trials involving adoptive T cell therapy using genetically modified T cells. Patient's blood lymphocytes are harvested through apheresis and engineered through the insertion of an antigen-specific artificial T cell receptor (called chimeric antigen receptor or CAR). The CAR-engineered T cells are thereby enabled to seek out a tumor antigen on the surface of ovarian cells and kill them. A large number of such CAR-engineered T cells can be expanded in culture and prepared for infusion. Once the patient enrolls, she receives three days of chemotherapy, followed by infusion of her own activated lymphocytes in combination with cytokine therapy. There are several known ovarian cancer associated antigens including the folate receptor- alpha, mesothelin and NY-ESO-1.
T-cells are engineered to target a specific receptor known as alpha folate receptor (aFR), which is over-expressed on 90 percent of ovarian cancers but not highly expressed by normal tissues. In pre-clinical tests, engineered cells were injected into the bloodstream of mice with established ovarian tumors. Dramatic anti-tumor responses were reproducibly achieved after the mice received an infusion of aFR genetically engineered T-cells. This exciting pre-clinical work was performed in Dr. Daniel Powell's laboratory at the OCRC. For more information on the preclinical work please visit http://www.uphs.upenn.edu/news/News_Releases/2011/08/ovarian-cancer/
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We are preparing to launch this study at the end of 2011 and aim to recruit up to 21 patients with advanced recurrent ovarian cancer whose tumors express the alpha folate receptor.
The researchers of at the OCRC have also joined forces with the laboratory directed by Carl June, MD to launch two trials using genetically engineered T cells targeting mesothelin and NY-ESO-1.
Dr. Janos Tanyi is now the Principal Investigator of Immune Therapy Trials at Penn
Janos L. Tanyi, MD PhD joined the Department of Obstetrics and Gynecology and the Division of Gynecologic Oncology as an Assistant Professor in 2011. His clinical research focuses on the identification oftranscriptional and translational differences associated with the presence or absence of antitumor immune response in ovarian cancer. Dr. Tanyi received his medical degree at the University of Debrecen, Medical and Health Sciences Center in Hungary, summa cum laude. He completed his residency training in obstetrics and gynecology at the Baylor College of Medicine in Houston, and subsequently, a gynecologic oncology fellowship at Penn Medicine. Dr. Tanyi has been working closely with Dr. Coukos and we are happy to announce that Dr. Tanyi is now the Principal Investigator of two of the immune therapy trials at Penn.
The Ovarian Cancer Research Center (OCRC) has treated 15 patients enrolled in the vaccine clinical trial. Each patient receives a personalized vaccine developed from the patient’s own tumor and blood cells. This vaccine uses a new and unique platform, which was developed in the OCRC laboratory and introduced for patient care by the OCRC clinical team.
We are pleased to announce the opening of a third trial, which combines chemotherapy, anti-angiogenic therapy and vaccine therapy. We believe that this combination will prove to be synergistic and therapeutically powerful. Patients will the have the ability to maximally benefit from these three agents in combination.
Active Clinical Trials
For a complete listing of all active clinical trials, please visit: http://www.uphs.upenn.edu/obgyn/clinical-trials/
For more information please contact our Clinical Team at (215)615-7447 or OCRC.Trials@uphs.upenn.edu
Regional Ovarian Cancer Network—Tumor Storage
The OCRC is expanding throughout the tri-state region to offer treatment options to women with ovarian cancer. We have established a Regional Ovarian Cancer Network (ROCN) and Ovarian Tumor Processing Facility.
Many patients learn about the immunotherapy program at Penn Medicine when it is too late. Most patients don't know that they need to have their tumor collected and saved at the time of initial surgery. In fact, often by the time they contact Penn Medicine, they have already had surgery, their tumor has been discarded and vaccine and cell-based therapy is no longer an option.
Under this new program, a patient who has surgery at her local hospital can have her tumor tissue shipped to the OCRC, where it is processed and stored live for future immunotherapy. The patient will be able to receive immunotherapy after completion of standard-of-care therapy (surgery and chemotherapy) in the community.
For more information please contact our clinical Team at (215)615-7447 or OCRC.Trials@uphs.upenn.edu
Ovarian Cancer Research Center Clinical Immunotherapy Development Group
- George Coukos, MD, PhD
- Janos Tanyi, MD, PhD
- Lana Kandalaft, PharmD, MTR, PhD
- Daniel J. Powell, Jr., PhD
Ovarian Cancer Research Center Clinical Staff
- Melissa A. Moore, CRNP
- Kathleen Steacker, RN
- Sureya Sufian, RN
- Jessica Marchesi
- Gabor Kari
- Klara Balint
- Andrew Best
- Daniel Schullery
- Qunrui Ye
- Vijaya Dandamudi
Gynecologic Oncology Fellows
- Emese Zsiros MD, PhD
- Stephanie Jean, MD
- Ashley Ford, MD
- Caitlin Stashwick, MD
- Nawar Latif, MD
Our Extended Clinical Team
- Mark A. Morgan, MD
- Edward A. Stadtmauer, MD
- Lilie Lin, MD
- Bruce Levine, PhD
- Virginia A. LiVolsi, MD
- Kathy Montone, MD
- Michael Feldman, MD
- Donald L. Siegel, MD, PhD
- Daniel Sterman, MD
- Drew A. Torigian, MD
- Mark Rosen, MD
- Harvey L. Nisenbaum, MD, FACR, FAIUM, FSRU
- Stephen Shuster, MD
- Jacub Svoboda, MD
- Nancy Gilinger, RN
- Phylis, Croshaw, LPN
- Patricia Murphy, LPN
- Marcella Rominiecki-Sananta, RN
Ovarian Cancer Research Center Preclinical Immunotherapy Development Group
- George Coukos, MD, PhD
- Ron Drapkin, MD, PhD
- Andrea Facciabene, PhD
- Janos Tanyi, MD, PhD
- Daniel Powell, PhD
- Lana Kandalaft, PharmD, PhD
- Aizhi Zhao, PhD
- Chunsheng Li, PhD
- Chongyung Fang, PhD
- Yadi Omidi, PharmD, PhD
- Jaleh Barrar, PharmD, PhD
- Wei-Ting Hwang, PhD
- Lin Zhang, MD
