WHY AN IMMUNE THERAPY CLINICAL APPROACH?
The immune system specializes in surveying and protecting the body from cancer cells, viruses, bacteria, and other disease-causing pathogens. Dendritic cells are blood cells that specialize in surveying the body to identify foreign intruders, pathogens or cancer cells and instruct the body’s killer-T cells to attack it. Once T-cells are activated against the tumor, they infiltrate the tumor and try to attack.
Recent research demonstrates that the human immune system naturally recognizes and attacks cancer cells as evidenced by the presence of tumor-specific killer T-cells within dissected tumors. More importantly, relatively higher concentration levels of tumor-specific killer T-cells within the patient’s tumor appear to be correlated with improved patient outcome. The problem is that this natural self-defense effort mounted by the human immune system is typically not delivered with sufficient force to combat cancer cell proliferation.
The immune system appears to deploy the correct soldiers for the fight, but it deploys a woefully inadequate number of them. In approximate terms, only one-half of one percent of an ovarian cancer patient’s killer T-cells are programmed to attack her tumor, unless the immune system is otherwise instructed to take more aggressive action.
AUTOLOGOUS IMMUNOTHERAPEUTIC VACCINES
Immunotherapeutic vaccines seek to increase the immune system’s attack on the patient’s cancer by intensifying the same interaction between scout cells and killer cells that occurs in nature. The dendritic-cell therapeutic vaccine that the ITI-OC is supporting takes the natural attack function of the immune system and amplifies it, thereby focusing a much higher percentage of the patient’s immune system on her ovarian cancer.The ultimate objective of these immune system-based cancer vaccines is to direct a larger percentage of the patient’s killer T-cell army against his or her specific cancer. As described below, dendritic cells are the most effective leverage point within the immune system to achieve that objective.
The ovarian vaccine currently being tested in a clinical trial at the University of Pennsylvania is a so-called “autologous” vaccine. Autologous vaccines represent one of the most natural of all vaccine designs because their major components are exclusively derived directly from the patient herself. Autologous vaccines use the patient’s own tumor tissue is to educate and direct the patient’s own dendritic cells which, in turn, deploy more of the patient’s own tumor-specific killer T-cells to attack the cancer.
The autologous dendritic cell vaccine is produced in two sequential steps:
Step 1. Breeding and Programming Dendritic Cells
A very powerful way to make cancer vaccines is by manufacturing dendritic cells in the laboratory. This process is now very well characterized. Blood cells from the patients are harvested through a blood donation process called leukapheresis Hundreds of million of dendritic cells can be prepared by a single leukapheresis from a single patient. These are ”blank” dendritic/scout cells (i.e., cells that have not yet selected any target).
To generate a cancer vaccine, dendritic cells are then mixed with the patient’s own tumor material, which has been harvested during prior surgery. The tumors are processed immediately after surgery in the laboratory to isolate tumor cells. When dendritic cells are exposed to the patient’s tumor cells as their target, these dendritic cells react as if they had discovered the patient’s disease while going about their ordinary scouting business inside the body. They record the unique detail of the patient’s tumor, thereby programming themselves to instruct the patient’s killer T-cells to attack the cancer.
Step 2. Activation of Killer T-Cells
This vastly expanded force of target-educated dendritic cells (now marked with the patient’s own tumor characteristics) is then re-injected into the patient in a sequence of shots over several months. When injected back into the patient, these dendritic cells apply powerful leverage within the immune system. They travel to the local lymph nodes where each dendritic cell instructs and deploys up to 1,000 killer T-cells to attack the patient’s specific cancer. The result is a significant increase in the power and precision of the immune system’s assault on the disease.
Safety is typically not an issue with autologous vaccines because they are based on the patient’s own cells and tissue rather than antigens or other materiel that is not naturally occurring. Hundreds of patients with various cancers have been treated with multiple injections of autologous vaccines with no adverse effects. A red, itchy injection site is the most typical adverse reaction. The typical side effects of chemotherapy such as nausea, debilitating fatigue, hair loss, bone marrow suppression etc. are not seen with cancer vaccines.
UNIVERSITY OF PENNSYLVANIA: OVARIAN CANCER RESEARCH CENTER (OCRC)
The Ovarian Cancer Research Center (OCRC) was launched in July 2007 under the leadership of George Coukos MD. Ph.D. OCRC is focused on immune biology and immune therapy of ovarian cancer and has found that a spontaneous immune response against cancer influences the course of the disease. Specifically, Penn’s research was the first to discover that the presence of certain immune cells, tumor infiltrating T-cells, can predict an improvement in the outcome of patients with advanced ovarian cancer.
- Penn researchers identified the presence of tumor-infiltrating T-cells in 102 of 186 women with ovarian cancer tumors. Among the advanced ovarian cancer patients with these T-cells, 38 percent were alive five years after their cancer diagnosis while only 4.5 percent of the women without these T-cells were still alive.
- Among the patients who received aggressive chemotherapy, those who had tumor-infiltrating T-cells were more likely to survive than patients without T-cells. A subset of patients who had optimal surgical resection, complete response to chemotherapy, and evidence of anti-tumor response, experienced up to a 70 percent survival at 10 years – a remarkable survival rate for advanced ovarian cancer. New England Journal of Medicine, January 16, 2003
- This finding has now been confirmed by several recent studies in the US, Canada, Europe and Japan.
Dr. Coukos and members of the OCRC have launched the first therapeutic vaccine trial for patients with ovarian and peritoneal cancer. The OCRC team is also now investigating why some patients' immune systems attack tumors while others do not. The answer could improve ovarian cancer survival outcomes by yielding new treatment modalities that induce anti-tumor responses in the later group.
Additional therapies are under development in Dr. Coukos' laboratory including autologous whole tumor antigen vaccines prepared from dendritic cells or tumor cells harvested from patient’s own tumor; new vaccines directed against the tumor stroma and blood vessels; T-cell therapies using autologous tumor-derived T cells or blood T cells engineered to attack tumor vessel targets; and combination therapies aimed at increasing tumor response to immune therapy. Dr. Coukos anticipates that in the future, immunotherapy in combination with surgery and chemotherapy will become a standard of care for ovarian cancer.
The Ovarian Cancer Research Center encompasses both (A) Translational and (B) Clinical research programs for ovarian cancer.
- The Translational Research Activities of the OCRC encompasses:
- The ovarian cancer advanced therapeutics program. New treatment approaches are developed to increase women’s chances for cure with emphasis on immune and gene therapy.
- The ovarian cancer early detection and prevention program. New detection serum diagnostics (blood tests) and molecular imaging technologies, as well as new prevention methods are being developed.
- The ovarian cancer biology and pathogenesis program. This has a more fundamental discovery focus, with the aim to understand the pathogenesis and biology of ovarian cancer and feed the other two programs with ideas and information from which detection, prevention and therapeutic tools can be developed.
Members of the Translational Research team comprise Drs. George Coukos, Lin Zhang, Nathalie Scholler, Daniel Powell, Andrea Facciabene, Phyllis Gimotty and Carl June. The extended research group includes more than 40 full time employees in the laboratory such as post-doctoral researchers; rotating clinical fellows; PENN graduate students; medical students; visiting foreign graduate students; visiting scientists; and support technical personnel.
- The Clinical Research Program is a worldwide pioneering program for ovarian cancer therapy. Members of OCRC aspire to improve patients’ clinical responses and reduce toxicity from current chemotherapies by developing new immune therapy, gene therapy and combination therapy approaches. The OCRC clinical team comprises Drs. George Coukos, Christina Chu, Lana Kandalaft , Stephen Rubin and Daniel Powell.
A ovarian cancer dendritic cell vaccine trial has already been completed at Penn, where patients completing chemotherapy have received autologous dendritic cells loaded with tumor antigen HER2 and hTERT peptides.
Currently we have a new dendritic cell whole-tumor antigen vaccine open. This uses tumor lysate-pulsed autologous dendritic cells in combination with bevacizumab and oral metronomic cyclophosphamide. This is an entirely autologous patient-tailored immune therapy strategy. Patients completing this therapy can enroll in a following study which will test the feasibility, safety and clinical efficacy of of adoptive T-cell therapy in which a patient’s T-cells, harvested from her own white blood cells after completion of the vaccine, are primed and expanded in the laboratory, and ultimately reintroduced to the patient through transfusion to help fight the patient’s tumor. The expansion and activation of T cells in the laboratory hopes to magnify the immune response against the tumor and achieve more powerful results after completion of the vaccine. Other studies include combination chemo-immunotherapy clinical studies where conventional chemotherapy or cytokine therapy.
Currently in development is a gene therapy trial in collaboration with BioCancell Inc. This trial uses DTA-H19 DNA, a DNA molecule that is administered intraperitoneally and is picked up by the tumor cells, where it uses the tumor’s unique molecular machinery to turn on a lethal toxin derived from the Diphtheria bacteria. This is ex[pressed selectively in tumor cells because it exploits unique genes that tumor cells express, and kills selectively the tumor cells. This therapy is hoped to improve the quality of life of patients with fluid in their abdomen.
The OCRC plans to launch additional clinical protocols stemming directly from the work in the lab. For example, we propose a Phase I trial of adoptive therapy using tumor infiltrating lymphocytes (TILs). The proposed trial will test the feasibility and safety of expanding TILs from ovarian tumors rescued surgically and administering them at completion of conventional carboplatin/paclitaxel. In addition, we have generated a number of tools and combinatorial approaches targeting the tumor microenvironment that need to be tested urgently in the clinic. We expect that within the next 2 to 3 years, we will bring to the clinic one or more of these concepts. Additionally, an active research development program is optimizing lymphocyte engineering and we will bring to the clinic the first clinical study with autologous lymphocytes genetically engineered to kill ovarian cancer cells expressing mesothelin, developed in the laboratory of Carl H. June, MD. In summary, we are in the unique position to bring to the clinic innovative tools and combinatorial approaches for cancer immunotherapy.