The following represents a layman’s description of the ovarian vaccine-based immunotherapy currently being tested for ovarian cancer in a clinical trial at The University of Pennsylvania (Abramson Cancer Center). The full clinical trial protocol is available upon request.
Vaccine Mechanism of Action
The immune system is the body’s defense mechanism responsible for recognizing and eliminating cancer cells, viruses, bacteria, and other disease-causing organisms. Dendritic cells are the scouts of the human immune system, effectively acting as the guidance mechanism for the body’s immune defenses. These specialized scout cells travel through the blood stream looking for whatever infections or diseases they can find. When they discover an intruder, these scout cells capture data on that intruder and instruct the body’s killer-T cells to attack it.
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.
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 vaccine that we are 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 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.
Making the Vaccine
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 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
“Blank” dendritic/scout cells (i.e., cells that have not yet selected any target) are identified and collected from the patient’s blood through a filtration process called leukapheresis. These blank dendritic cells are bred (ex-vivo) in the laboratory, vastly increasing their numbers.
This expanded cohort of blank dendritic cells is then exposed to the patient’s own tumor tissue which has been harvested during prior surgery. When they are exposed to the patient’s tumor tissue as their target, these dendritic cells behave 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, with each dendritic cell instructing and deploying 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.
A simplified illustration of this two-step process is provided below.
Origins of the Vaccine Project
In identifying this particular therapeutic vaccine design for philanthropic support, the co-founders of the Ovarian Cancer Vaccine Initiative sought advice from more than a dozen of the most prominent cancer centers in the U.S. and abroad. Many of the thought-leaders in the oncology community highlighted the immune-system research being conducted at The University of Pennsylvania (Abramson Cancer Center). The names of Drs. George Coukos and Carl June were repeatedly referenced, even by their theoretical rivals for research grants.
Discussions with Dr. Coukos and the Abramson Cancer Center’s team confirmed that they had a longstanding interest in finding a corporate partner with whom to launch an ovarian cancer immunotherapy trial. They also expressed a strong preference for anchoring that trial with an autologous dendritic-cell vaccine.
It was determined that Northwest Biotherapeutics Inc., a small Seattle-based biotechnology firm, had developed the requisite dendritic-cell technology for designing and producing autologous, “whole tumor” cancer vaccines. The vaccine technology developed by Northwest Biotherapeutics traces its origins to the pioneering work of Dr. Gerald Murphy (former Chief Medical Officer of the American Cancer Society) and Dr. Haakon Ragde (often referred to as the “father of brachytherapy”, a methodology for treating prostate cancer).
The UPenn and Northwest Biotherapeutics teams were introduced and formed a joint task force to develop a state-of-the-art immunotherapy protocol for treating recurrent ovarian cancer. Northwest Biotherapeutics generously agreed to permit the use of their intellectual property and access to their FDA filings. They also agreed to support this program by providing the vaccine at no cost and by contributing a wide range of infrastructure and support services. The team at The Abramson Institute contributed substantial amounts of un-reimbursed research time and expertise in support of the vaccine design, definition of the trial structure and protocol, producing the documentation required for trial approvals, etc.
This joint project development team concurred that an autologous, whole-tumor lysate design represented the ideal platform for their vaccine. They also agreed that co-administration of chemotherapy along with the vaccine was desirable for the reasons outlined below.
The immune system is enormously powerful, but ramping it up is a slow process. In the initial stages of vaccine immunotherapy, one of the greatest risks is that the cancer will re-establish itself before the immune system can be stimulated to adequate levels of efficiency. Consequently, it was agreed that the vaccine induction period should be supported with chemotherapy to hold recurrent disease in check while the vaccine increased the immune system’s concentration of killer T-cells.
A cocktail of Avastin and low-dose Cytoxan was chosen for this purpose, and this therapy is currently being administered along with the vaccine as part of the trial protocol. In addition to retarding the growth of recurrent disease during the immune system “ramp-up” period, UPenn’s research suggests that these drugs may also be synergistic with the vaccine by assisting the immune system’s attack within the patient’s tumor.
Vaccine Trials Now Underway
The Phase I clinical trial resulting from the collaborative effort between these two organizations is now underway at The University of Pennsylvania. Within the next few months, it is anticipated that The UCSF Medical Center in San Francisco will become the west coast site for this clinical trial. In total, 36 patients will be enrolled in the trial.
Will This Vaccine Be Effective?
No cancer therapy comes with a guarantee, but this vaccine-based protocol has an impressive track record. This same vaccine design has more than doubled survival rates and progression-free survival duration in glioblastoma patients. These glioblastoma results represent an encouraging test case because it is one of the most virulent forms of brain cancer…a near-term “death sentence” disease with a lethal reputation matching that of pancreatic cancer.
The results of the UCLA/Northwest Biotherapeutics’ FDA Phase I glioblastoma vaccine trial have been enormously encouraging. Of the 19 patients treated in this trial, 9 are still alive with an average survival of nearly three years…a statistic that will improve as these patients continue to live. Most of the surviving patients have no evidence of tumor recurrence, and 4 of the 9 remaining patients have survival times without progression or recurrence that extend to nearly four years. These results are extraordinary in the context of glioblastoma, where expected survival is typically measured in months.
The ovarian cancer vaccine being administered in the current University of Pennsylvania clinical trial is virtually identical in design to the vaccine used in the UCLA/Northwest Biotherapeutics glioblastoma trial.
Safety
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.
As an example of the benign toxicity profile of these vaccines, Northwest Biotherapeutics has treated more than 100 cancer patients (prostate and glioblastoma) with multiple injections of its dendritic-cell vaccines, with no material adverse effects. A red, itchy injection site is the most typical adverse reaction. No nausea, no debilitating fatigue, no hair loss, etc. This experience mirrors the typical toxicity experience of other institutions using or testing therapies based upon autologous components.
Related Research Initiatives
The mission of The Ovarian Cancer Vaccine Initiative is to finance the vaccine trial described above. However, if available funds permit, we would also intend to provide support for research at UPenn’s Abramson Cancer Center which specifically seeks to improve or expand the applicability of this ovarian cancer vaccine.
The Abramson Institute research team has identified several approaches to producing a dendritic cell-based vaccine for patients who cannot contribute the solid tumor tissue currently required for autologous vaccine manufacture. For example:
- extracting tumor-specific T-cells from malignant ascites (the cancer-bearing abdominal fluid that frequently develops in ovarian cancer patients); or,
- extracting lysate from a multi-factorial ovarian cancer cell line to generate an off-the-shelf “universal” vaccine that is not patient-specific.
In addition, the evaluation of different vaccine/chemotherapy combinations might improve the vaccine therapy by allowing customized vaccine/chemotherapy combinations for patients who are either particularly resistant to or highly responsive to specific chemotherapy agents.
Stage-2 Follow-on Trial
The UPenn/Northwest Biotherapeutics project team is also designing a follow-on vaccine trial which would add an additional therapeutic component seeking to further increase the patient’s level of tumor-specific killer T-cells.
As previously noted, the ultimate objective of cancer immunotherapy is to cause large numbers of tumor-specific killer T-cells to attack the patient’s cancer. A broad philosophy embedded in the immunotherapeutic process is that, within reason, the more tumor-specific killer T-cells targeting the patient’s cancer, the better the expected outcome.
The University of Pennsylvania’s research team has developed a proprietary methodology for isolating and expanding a patient’s tumor-specific killer T-cells. This process is referred to as “adoptive T-cell transfer” and is analogous to the expansion of dendritic cells in the laboratory which forms the basis for Northwest Biotherapeutics’ dendritic cell vaccine. The patient’s blood is drawn and her tumor-specific killer T-cells are isolated. These cells are bred up ex-vivo, and the resulting, expanded cohort of killer T-cells is re-injected into the patient.
This adoptive T-cell transfer process does not replace the initial vaccine therapy, but is additive to it. When delivered as a second stage of therapy following vaccine treatment, adoptive T-cell transfer is expected to generate even higher levels of tumor-specific killer T-cells within the immune system than dendritic-vaccine treatment could achieve on its own.
The critical question facing the vaccine-development team is whether this adoptive T-cell transfer process is additive to the initial therapeutic results that can be delivered by the vaccine. Only a well-designed, randomized clinical trial can produce the answer to the question of whether “more is better”.
To resolve this question, the UPenn/Northwest Biotherapeutics team is considering the following design for a two-stage cancer immunotherapy protocol combining the best of their respective technologies:
- The Northwest Biotherapeutics autologous dendritic cell vaccine would be used to prime the immune system, boosting the blood concentration of tumor-specific killer T-cells from ½% (the therapeutically inadequate natural level) to 5% or more.
- This vaccine therapy would then be followed by a further “turbocharge” of additional tumor-specific T-cells enabled by UPenn’s proprietary, adoptive T-cell transfer technology, thereby increasing the patient’s tumor-specific T-cell force to even higher levels.