We implemented our application process in June, sending Request for Applications (rfa) to every medical institution and major cancer

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1 Spring 2003 Number 1 Volume 1 ACGTSequence THE NEWSLETTER OF THE ALLIANCE FOR CANCER GENE THERAPY FROM THE EXECUTIVE DIRECTOR the awards of our first young investigator grants in november to three extraordinary young scientists, involved in the newest emerging strategies for gene therapy research, are a moment of great promise for us at the Alliance for Cancer Gene Therapy. It represents a significant way in which we can participate in the war against cancer. Inside: Details on Our 2002 Grant Winners Gene Therapy in the News Five Reasons to Support ACGT Each of the scientists awarded our Young Investigators Grants, is pursuing a different path for cancer gene therapy research: anti-angiogenic gene therapy targeted at neuroblastoma, a deadly form of childhood cancer; immunotherapy/vaccine therapy for prostate cancer; and tumor targeting/vector development, a gene therapy delivery vehicle for ovarian cancer. We are sure you will find their research projects compelling, but more importantly, the potential for broader applications from their research to fight all cancers. Their stories are all inside. From a June launch to a nationally recognized foundation in just eight months The announcement of our grants concludes a very productive beginning for the Alliance for Cancer Gene Therapy (acgt). We are now a nationally recognized charitable foundation, the only one dedicated exclusively to the funding of cancer gene therapy research. What a difference a few months makes! We implemented our application process in June, sending Request for Applications (rfa) to every medical institution and major cancer Edward Netter and Barbara Netter, founders of ACGT; Margaret Cianci, Executive Director; and Dr. Savio Woo, Chairman of the Scientific Council research center in the country. We received 45 proposals for significant research projects from 27 nationally accredited institutions and major cancer research centers including Johns Hopkins University, Rockefeller University, Children s Hospital Los Angeles, Albert Einstein College of Medicine, Vanderbilt University, University of Chicago, University of California, M.D. Anderson and more. Taking the application process further We modeled our application and peer review system on the successful standard established by the National Institute of Health, but took it one step further. Our entire application process went on-line through the acgt web site; all proposals were submitted electronically. In November, we convened the Scientific Council and Board to select our recipients. We are most appreciative of the support and cooperation of the peer reviewers, the acgt Scientific Council and Board, and Allison Neslage, who recently joined us as marketing manager and coordinated this complex process. Sequence, our first newsletter, is the beginning of a dialogue with you about gene therapy research and acgt s plans for the future. You are a part of acgt s founding. We hope that you will support the vital promise of gene therapy in the fight against all forms of cancer. You are helping to save lives. Best regards, Margaret Cianci, Executive Director The first ACGT Grant Winners announced! See inside for complete details.

2 Members of the Scientific Advisory Council Dr. Stuart Aaronson; Dr. Michael Lotze; Dr. Savio Woo, Chairman; Dr. Thomas Wickham; Dr. Wen-Hwa Lee; Dr. Lie-Ping Chen < 2002 Grant Recipients acgt provides grants to scientific researchers at academic institutions throughout the united states for specific gene therapy projects in the following areas: Anti-angiogenesis Tumor-Specific Replicating Viruses and Bacteria Immunotherapy/ Vaccine Therapy Oncogenes/Suppressor Oncogenes/Cell Cycle Control/Apoptosis Tumor Targeting/Vector Development the grants are awarded on two levels: Young Investigator Awards Typically tenure-track Assistant Professors, within five years of their initial appointment to this rank. Recipients can receive a maximum of $500,000 distributed over three years, inclusive of a maximum of 10% indirect costs. ACGT s first awards are to Young Investigators for research applicable to Anti-angiogenesis, Immunotherapy/Vaccine Therapy, and Tumor Targeting/ Vector Development. Investigators Awards Investigators are Associate and Full Professors. Distribution is made upon availability of funds up to $1,000,000 over three to five years, and is inclusive of a maximum of 10% indirect costs.

3 Anti-angiogenesis directed at Neuroblastoma Angi-angiogenesis is the process of new blood vessel formation. It is essential for cancer progression because tumors need nutrients, which are supplied by the blood, to grow. In addition, new blood vessels provide a route for cancer cells to escape and spread throughout the body. The goal of anti-angiogenic therapy is to prevent blood vessels from growing in support of tumor progression. It is hoped that anti-angiogenesis agents will prove effective for the treatment of cancers that have become resistant to conventional chemotherapy and other anti-cancer agents, with broad potential to treat most, if not all, forms of cancer. Andrew M. Davidoff, M.D. St. Jude Children s Research Hospital Memphis, Tennessee Dr. Andrew Davidoff is a Board certified pediatric surgeon at St. Jude Children s Research Hospital in Tennessee. His extensive clinical and research interests in pediatric oncology have led him to pursue investigation into antiangiogenic treatment, using gene therapy as a central delivery strategy for neuroblastoma. M.D., University of Pennsylvania School of Medicine Assistant Member, Department of Surgery, St. Jude Children s Research Hospital Appointments to the Divisions of Transplantation, Gene Therapy and Experimental Hematology Assistant Professor of Surgery and Pediatrics, University of Tennessee College of Medicine Member, Children s Oncology Group (COG) and Vice-Chairman of the Young Investigator Committee of COG Research Focus The development of anti-angiogenic gene therapy for the treatment of patients with neuroblastoma, a deadly form of childhood cancer. Neuroblastoma is one of the most common childhood cancers. New treatment strategies are urgently needed because the prognosis for most children with this particular form of cancer is poor. Fighting Neuroblastoma In the years I have been at St. Jude, I have seen many children with neuroblastoma die. Current therapy for neuroblastoma includes aggressive chemotherapy, surgery and radiation therapy. The results are often unsatisfactory, and the prognosis for these patients has not really changed much over the past twenty to thirty years. Clearly, new ideas are essential to improve the outcome for these children. I believe emerging anti-angiogenesis strategies present exciting new possibilities for more effective treatment. Angiogenesis, the formation of new blood vessels, is a process central to cancer progression. Inhibition of angiogenesis represents a promising new approach to limit the formation of new blood vessels, essentially starving a growing tumor. This approach is very likely to have broad applicability to most, if not all types of cancer, beyond neuroblastoma. The hypothesis for my research, conducted in collaboration with other researchers at St. Jude Children s Research Hospital, is that liver-targeted delivery of the gene for pigment epithelium derived factor (pedf), a very potent angiogenesis inhibitor, can inhibit angiogenesis, thereby restricting neuroblastoma growth. pedf offers a dual function not only can it inhibit angiogenesis, but it can also induce the maturation of neuroblastoma cells, thereby decreasing their malignant potential. Viral vectors will be used for gene delivery, as they have been shown to safely deliver the gene of interest to the liver, with minimal side effects over time. The primary goal of our research is to demonstrate that gene therapy techniques can be safely and effectively used to deliver angiogeneisis inhibitors as part of an anti-cancer treatment strategy. When this research is completed, it is our hope that there will be sufficient preclinical data to justify and support a clinical trial in cancer patients using this form of gene therapy. Mission of ACGT: To fund innovative scientific research into the causes, treatment and p

4 Tumor Targeting/Vector Development directed at Ovarian Cancer Critical to the effectiveness of gene therapy strategies is the development of technology to deliver therapeutic genes specifically to target cells. One of the most beneficial aspects of cell and gene-based medicines lies in their ability to directly target cancer cells, enhancing their effectiveness, safety, and also reducing side effects. These therapeutic genes can be directed to target cells in a variety of ways through gene delivery vehicles known as vectors (derived from the Latin word to carry ). Delivery methods include the use of disarmed viruses or synthetic vehicles. Jeffrey S. Bartlett, Ph.D Columbus Children s Research Institute Columbus, Ohio Department of Pediatrics The Ohio State University Ph.D., Molecular Biology, University of Pittsburgh School of Medicine Columbus Children s Research Institute Assistant Professor, Department of Pediatrics, The Ohio State University Dr. Jeffrey Bartlett is a researcher at Columbus Children s Research Institute. His project explores the potential of a common human virus as a gene therapy vehicle directed at ovarian cancer. Research Focus The development of an efficient and specific gene therapy delivery vehicle for patients with ovarian cancer. Ovarian cancer is a frightening diagnosis for women, since symptoms frequently do not manifest until the late stages of the disease, for which a cure remains elusive. This is one of the most common malignancies affecting women in the United States, the other two common forms being breast and lung cancer. Approximately 25,000 cases will be diagnosed this year, and more than 15,000 women will die. Fighting Ovarian Cancer Although gene therapy has emerged as an exciting experimental approach for the treatment of ovarian cancer, crucial to its success will be our ability to deliver therapeutic genes efficiently and specifically to tumor cells in the patient. Our research, for which we have been developing preliminary data and rationale in my laboratory for the past three years, will focus specifically on these two aspects. By rearranging the genetic structure of a common human virus, known as adeno-associated virus or AAV, we have developed a class of viruses that will, in effect, function as molecular Trojan horses, delivering therapeutic genes to a specific population of cells. These Trojan horse viruses, which are called vectors, have been engineered to target ovarian cancer cells by introducing key sequences into the virus shell that permits the virus to infect only those cells that display a corresponding lock, a cell-surface marker that is restricted to cancer cells. These particular vectors are both more efficient and more selective than current gene delivery vehicles. Our first step will be to develop and test these agents in the laboratory. We will then test the ability of these special vectors to cure ovarian cancer in mice. If these studies prove successful, human trials would be proposed for the future. My involvement in this particular aspect of research came about when Dr. Wenfang Shi joined my laboratory three years ago. Dr. Shi is clinically trained in obstetrics and gynecology and was intrigued by developing a gene-based treatment for ovarian cancer. Although this treatment was far from my realm of expertise at the time, Dr. Shi s vision and persistence became the driving force behind this project. My own sense was that ovarian cancer would be a good candidate for gene therapy, and that women with advanced stage disease desperately need another alternative. Previously, we attempted to deliver genes to the mesothelium, the tissue lining of the peritoneal cavity, as part of another project in the laboratory. The results were disappointing. However, the research did suggest that vectors administered to the peritoneal cavity might spare normal mesothelial tissue while delivering and expressing genes in ovarian tumors which often grow here. This second stage is now the focal point for our work. Mission of ACGT: To fund innovative scientific research into the causes, treatment and prevention of all types of cancer, utilizing cells and genes as medicines. revention of all types of cancer, utilizing cells and genes as medicines.

5 Immunotherapy/Vaccine Therapy directed at Prostate Cancer Tumor cells function differently from normal cells and, therefore, should be recognized as foreign by the body s immune system and rejected. Unfortunately, tumor cells have acquired the means to deceive the immune system into thinking they are normal cells and prevent the immune system from destroying them. Introducing genes to a tumor can activate the immune system or counteract the tumor s ability to disarm the immune system, which can result in tumor rejection and tumor-free survival for the patient. Vaccines and other immunotherapies, using gene therapy as the delivery mechanism, can train the body s immune system to go after cancer cells. Thomas S. Griffith, Ph.D. Assistant Professor, Urologic Oncology University of Iowa Dr. Thomas Griffith is an assistant professor in the Department of Urology at the University of Iowa. The expectation is that his current research on Ad-5 TRAIL will move to a Phase 1 clinical trial at the University of Iowa within the year, in which he will collaborate with Badrinath Konety, M.D., also from the Department of Urology at the University of Iowa. B.A., Illinois Wesleyan University M.S., Illinois State University Ph.D., Washington University Postdoctoral training, Immunex Corporation Research Focus Development and testing of Ad5- TRAIL based gene therapy for future clinical trials in patients diagnosed with prostate cancer. Ad5-TRAIL is a unique, potent agent that induces tumor cell death. Prostate cancer is the secondleading cause of death from cancer among men in the United States. Current treatments are limited to radical surgery or radiation therapy for both localized tumors within the prostate and those that have spread into the abdominal organs. However, once the cancer has metastasized there is no cure, and treatment shifts to palliative therapy to ease the patient s symptoms. All therapies, for all stages, have difficult side effects. Fighting Prostate Cancer The long term goal of our research is to develop an effective treatment for prostate cancer. A unique apoptotic agent, trail, which is the acronym for tumor necrosis factor-related apoptosis-inducing ligand, acts as a means for inducing tumor cell death. Although many different agents, such as proteins, chemotherapies, or radiation can induce tumor cell death, they are commonly associated with terrible side effects that can compromise the health of the patient. trail is generating tremendous excitement in the scientific community because of its unique ability to kill a wide range of tumors, but not normal, noncancerous cells and tissues. The basic idea of the therapy will involve transferring the trail gene into a cell with Ad5-trail, which is a genetically engineered virus (also referred to as a viral vector) that has been rendered incapable of reproducing itself and carries the trail gene. Once inside, the vector will then utilize the cell s own machinery to produce the trail protein and induce tumor cell death. Previous studies in the laboratory using animals carrying experimental human prostate tumors have demonstrated the effectiveness of this form of gene therapy, resulting in the death of tumor cells. Our current efforts are to take these findings one step further, and that is to determine Ad5-trail s ability to activate systemic anti-tumor immune responses in well-defined experimental animal models. Furthermore, we are planning to investigate the anti-tumor activity of Ad5-trail when combined with chemotherapeutic agents or proteins known to stimulate immunological responses. Initially, we are targeting localized prostate cancer for the clinical trial because these tumors are easily accessed by well established techniques and are contained in a very small area. But we hope it will ultimately prove effective for metastasized prostate cancer. We also envision potential applications to other cancers such as melanoma or breast cancer tumors, which are relatively easy to reach as well. One hundred percent of all funds raised by ACGT goes directly to research.

6 Gene Therapy in the News recent advancements in the understanding of genes, how they work, and the promise they hold in unlocking many scientific mysteries are a frequent media stories these days. Gene therapy employs viruses to infuse healthy, therapeutic genes in cells. As a result, there is a risk that retroviruses may settle near a cancer causing gene with potentially adverse effect. This has happened recently to two individuals in gene trials in France. Dr. Savio Woo, Chairman of the acgt Scientific Council, professor and founding Director of the Carl Icahn Insitute for Gene Therapy and Molecular Medicine at Mount Sinai School of Medicine in New York puts this within the historical context of scientific research that precedes gene therapy. Dr. Woo states: The experience of other patients in gene therapy trials has been nothing short of miraculous. However, the two recent developments in France challenge the scientific community to address and improve gene therapy. This situation will galvanize the very best scientific minds and is precisely the reason why we continue to need support for research. This is the normal scientific process when a new class of medicine emerges; clinical trials are when we learn of the side effects and find ways to deal with them. Think about chemotherapy; if one adverse effect had stopped research, there would be no chemotherapy today, with countless lives lost as a result. Five Reasons to Support ACGT How ACGT Differs From Other Cancer Research Foundations 1. ACGT is the only foundation dedicated exclusively to cancer gene therapy research. 2. Cancer gene therapies have the potential not only to improve quality of life for those undergoing treatment, but also to effect a cure. The focus of ACGT research is clearly defined. 3. A Scientific Council, comprised of preeminent physicians and researchers in the field of cancer gene therapy, advises ACGT and vet all applications for grants. 4. Young Investigator Awards are designed to benefit young researchers who may not otherwise receive funding. Because the size of the ACGT grant is larger and its term longer than is typically granted to Young Investigators, the ACGT Young Investigators are able to spend more time on research rather than seeking additional funds. 5. ACGT, the research institutions, and the universities develop a unique relationship whereby ACGT recovers monies from any advancement that is directly attributable to the ACGT award. 100% of such funds are then used for additional grants. to request additional information and procedures for grant applications, or to make a charitable contribution, please contact us. BOARD OF DIRECTORS Edward Netter PRESIDENT John Adler Diane W. Darst Edward E. Hartline Dr. Swan Thung Peter C. Trent SCIENTIFIC ADVISORY COUNCIL Dr Savio Woo CHAIRMAN, SCIENTIFIC ADVISORY COUNCIL, MOUNT SINAI SCHOOL OF MEDICINE Dr Stuart Aaronson MOUNT SINAI SCHOOL OF MEDICINE Dr Lie-Ping Chen MAYO CLINIC Dr David Cheresh SCRIPPS INSTITUTE Dr Judah Folkman HARVARD MEDICAL SCHOOL Dr Wen-Hwa Lee UNIVERSITY OF TEXAS AT SAN ANTONIO Dr Michael Lotze UNIVERSITY OF PITTSBURGH Dr Robert Martuza HARVARD MEDICAL SCHOOL Dr Frank McCormick UNIVERSITY OF CALIFORNIA AT SAN FRANCISCO Dr Erkki Ruoslahti BURNHAM INSTITUTE Dr Thomas Wickham GENVEC, INC Margaret C. Cianci EXECUTIVE DIRECTOR Allison Neslage MARKETING MANAGER Barbara & Edward Netter FOUNDERS ACGT ALLIANCE FOR CANCER GENE THERAPY It is the linear sequence of the letters A, C, G and T from top to bottom along one of the two DNA strands that makes up the Genetic code of all genes National grants for cancer research Alliance for Cancer Gene Therapy Ninety six Cummings Point Road Stamford, Connecticut , ext fax