The LVR was formed in 2000 to address priorities in Vaccine Research that will potentially impact patient outcomes at City of Hope (COH) and other cancer centers world wide. In 2008, Dr. Diamond formed the TVR to expand the work started in the LVR towards additional tumor types and to accelerate clinical development of promising vaccine strategies. The foundation of the research priorities of the program grew out of the extensive collaboration with the Hematopoietic Stem Cell Transplant Program at COH, and the need for an effective therapeutic strategy for infections post-transplant (Tx). The infection that has historically played a major role in reducing the Tx success rate has been a herpes virus called cytomegalovirus (CMV). We started in 1993 to develop an immunologic approach for controlling this virus, and this work has continued. We have a two pronged attack on virus infection using two different but allied approaches for therapy. The first approach, relies on a non-living synthetic portion of the virus called a peptide, which will be given to the donor of the transplant to activate their immunity and provide protection from disease in the recipient in the process of giving them the stem cell products. This strategy is a partnership with the National Cancer Institute, and after eight years of preparative work, we anticipate submitting a final licensing document to the FDA in the summer of 2006 allowing us to initiate safety trials in human volunteers. The longer term goal of this process is to provide a therapeutic strategy for stem cell transplant patients at the City of Hope and other cancer centers world wide.

A second approach for a therapeutic CMV vaccine relies on a platform technology that was introduced into the LVR in 2001. This strategy relies on a weakened virus that has similarities to the smallpox vaccine. Its name is modified vaccinia Ankara or MVA. We are using this virus in a series of preclinical studies, many of which have already been published to substantiate its capacity to provide stimulated immunity against CMV and other viral agents. Recently, the National Cancer Institute awarded us a 5-year project funding as part of the large program originating in the Department of Hematology in which we will manufacture an MVA according to procedures that are acceptable to the FDA for clinical use. Clinical evaluation of this vaccine is anticipated in the next 5 years.

We have used a similar strategy in developing a CMV peptide vaccine in our program in HIV vaccine development. We have received exploratory funding awards from the Division of AIDS to support this research. The vaccine is based on a “fusion peptide,” a hybrid molecule engineered to contain peptide segments identical to key portions of HIV proteins. The hybrid molecule is engineered to contain peptide segments identical to key HIV proteins and general immune stimulators, and is designed to elicit a strong immune response against the virus. These segments are designed to elicit a strong and specific immune response against the virus, unlike vaccines based on attenuated virus or whole viral proteins, which present a complex target to the immune system. The immune system can respond in many ways to these conventional vaccines, not all of which may be protective. By using a synthetic vaccine with a limited number of target sites, the team hopes to make the immune response more targeted and more protective.

In the area of cancer vaccines, we are using the same technology for CMV utilizing the weakened small pox vaccine called MVA as a delivery vehicle for anti-cancer proteins that have been implicated in the body’s defense against tumors. Once again, we are partnering with the National Cancer Institute in developing this vaccine product that will be given clinically to City of Hope patients. This project is a collaboration with Dr. Joshua Ellenhorn, Staff Surgeon and Director of the Surgical Oncology Training Program at COH. The long term goal of this project is to provide a safer and milder form of therapy to post-operative cancer patients to prevent recurrence of deadly tumors that predictably recur after surgery. We anticipate clinical trials of this product in the next 2-3 years at COH in the Surgical Oncology Program.

CMV Vaccine Strategy
The Laboratory of Vaccine Research (LVR) is developing therapeutic strategies against CMV, HIV, and solid tumors using a variety of vaccine delivery strategies. For CMV, the vaccine will be used to protect immuno-compromised patients, such as those with AIDS or organ and bone marrow transplantation (BMT) recipients. Longer term, they are working on a second-generation vaccine to address the crisis of gestational CMV, ranked as the No. 1 American health problem that can be solved by a vaccine. In 2000, Dr. Diamond presented a summary of his studies to peer researchers at the Centers for Disease Control and Prevention (CDC) and the American Society of Hematology. The National Cancer Institute (NCI) also has provided funding for continued late-stage development. Now, armed with a contract to support evaluation of the vaccine manufactured under the auspices of the Rapid Access to Intervention Development (RAID) program of the NCI, the team is awaiting approval from the Food and Drug Administration to begin clinical testing. Safety testing of the vaccine in healthy volunteers is set to begin at City of Hope in the summer of 2006, to be followed by studies of its effects on patients with weakened immune systems, focusing on AIDS patients and BMT recipients.

Dr. Simon F. Lacey is using new molecular immunological tools and methods, including major histocompatibility complex (MHC) tetramer technology, to quantify cellular immunity to CMV in a cohort of bone marrow donors and recipients at City of Hope. By correlating incidence of CMV-reactivation and/or disease with the presence or absence of certain immunological parameters, the research team hopes to determine which of these are important for protection from CMV. The same techniques will be used to help assess the ability of the CMV peptide-based vaccine being developed in Dr. Diamond’s laboratory to induce CMV-specific immunity.

MVA as a Platform for Vaccine Delivery
We are using a vaccine delivery platform that is based on a highly crippled virus referred to as modified vaccinia Ankara or MVA. This crippled virus was developed in the 1970s as a safer alternative to the licensed vaccine for smallpox infection. It was developed in Europe and given to 120,000 high-risk children and elderly individuals to protect against potential smallpox outbreak. The NIH became interested in this virus in the early 1990s, and they continued to develop it as a potential vaccine delivery system for protection against a variety of pathogens. The infectious disease community took notice, and began exploring the properties of this virus as a vaccine for a variety of conditions, especially HIV infection. In the year 2000, we attended a meeting at Cold Spring Harbor Laboratory in New York, and heard extensively about the properties of this virus as a vaccine agent. Our laboratory arranged with the National Institute of Allergy and Infectious disease to provide us with the virus scaffold to insert genes from a variety of pathogens as well as tumor suppressor genes into the virus backbone.

CMV Vaccine
We developed an extensive program using genes from CMV as a starting point in our investigations of the property of the virus. These investigations have been quite successful, culminating in several milestones in the last year. These include transfer of a version of the MVA vaccine that will enable investigators at the University of Tübingen Medical Center to study its capability at stimulating T-cells against CMV in an adoptive transfer setting. At City of Hope, a project that is a component of the Hematology Program supported by the NCI was awarded five years of funding and received the highest merit rating of all of the projects included in the program. We recently developed a version of the MVA vaccine virus that incorporates CMV genes specific for Rhesus macaque, and are providing them to the University of California at Davis Regional Primate Center. They will test the ability of this vaccine to protect naïve individuals from exposure and infection with CMV from older animals who carry the virus. This will provide excellent feasibility data for the protective function of the vaccine in human subjects.

Cancer Vaccines
In collaboration with the Department of General and Oncologic Surgery, we have been conducting experiments in cancer immunotherapy for the past decade. We have taken a vaccination approach utilizing an attenuated poxvirus expressing either the human or murine forms of p53, a tumor suppressor gene. The immunization strategy we have used is taking place in immunocompetent mice, to best simulate a clinical situation. These mice are given large doses of tumor cells, and are subsequently vaccinated with the p53 gene in the attenuated poxvirus. In an exciting new development, we have also been introducing immune response modifiers to the mix, and have demonstrated significant attenuation of tumor outgrowth using the combined formulation. These developments culminated in the award of several grants to Drs. Diamond and Ellenhorn for clinical development and evaluation of a cancer vaccine using the MVA delivery vehicle as a platform. We have received funding to produce the virus under strict good laboratory practice (GLP) conditions in a designated room that was refurbished for this purpose with the help of City of Hope. Once this virus has been properly made and qualified, it will be provided to an outside company for clinical grade manufacturing. We will then seek FDA approval for this vaccine, and Dr. Ellenhorn will lead a clinical study to deliver the vaccine to adenocarcinoma patients who will be eligible in this first safety trial. We are excited about these developments and anticipate initiation of the vaccine trial in 2007.

HIV Vaccine Strategies
For HIV patients, a similarly designed vaccine to one being evaluated for CMV infection is meant to augment triple drug therapy in the short term, and eventually stimulate immunity. The team is developing a vaccine designed to stimulate the body’s long-term immunity to HIV and to enhance the effectiveness of triple drug therapy, with which nearly all AIDS patients are treated. While triple drug therapy greatly reduces viral load, research suggests that immune function is depressed by treatment. If the virus becomes resistant to drugs or if therapy is discontinued for any reason, researchers fear the weakened immune response could lead to rapid replication of the virus and the return of AIDS. By giving the vaccine in conjunction with triple drug therapy, the researchers hope to stimulate the immune system into continuing its attack on HIV. In the short term, the vaccine would augment triple drug therapy; in the long run, it would stimulate immunity. Its efficacy has been demonstrated in pre-clinical work, which has been and is still supported by Innovation Awards from the Division of AIDS of the National Institute of Allergy and Infectious Diseases.

Don J. Diamond, Ph.D.
City of Hope
1500 East Duarte Road
Translational Vaccine Research
Department of Virology
Fox South Building, Room 1000
Duarte, CA 91010-3012

Tel. 626-256-HOPE (4673)
Ext. 63450
Fax: 626-301-8981
ddiamond@coh.org