Galena Biopharma is focused on discovering, developing and commercializing innovative therapies addressing major unmet medical needs using targeted biotherapeutics.
Cancer Background
Cancer Represents a Significant Unmet Medical Need and Promising Commercial Opportunity
Cancer is a group of diseases characterized by either the runaway growth of cells or the failure of cells to die normally. Often, cancer cells spread to distant parts of the body, where they can form new tumors. Cancer can arise in any organ of the body and strikes one of every two American men and one of every three American women at some point in their lives.
Each year, nearly 1.6 million new cases of cancer are diagnosed in the United States, a figure that does not include the 1 million cases of skin cancer diagnosed annually. Cancer is the second leading cause of death (after heart disease) in the United States, expected to account for about 572 thousand deaths.
There are more than 100 different varieties of cancer, which can be divided into six major categories. Carcinomas, the most common type of cancer, originate in tissues that cover a surface or line a cavity of the body. Sarcomas begin in tissue that connects, supports or surrounds other tissues and organs. Lymphomas are cancers of the lymph system, the circulatory system that bathes and cleanses the body’s cells. Leukemias involve blood-forming tissues and blood cells. As their name indicates, brain tumors are cancers that begin in the brain, and skin cancers, including dangerous melanomas, originate in the skin. Cancers are considered metastatic if they spread via the blood or lymphatic system to other parts of the body to form secondary tumors.
Cancer is caused by a series of mutations, or alterations, in genes that control cells’ ability to grow and divide. Some mutations are inherited; others arise from environmental factors such as smoking or exposure to chemicals, radiation, or viruses that damage cells’ DNA. The mutations cause cells to divide relentlessly or lose their normal ability to die.
This year, one in four deaths in the US is expected to be due to cancer. For all forms of cancer combined, the 5-year relative survival rate is 64%. Despite the fact that the cancer mortality rate in the U.S. has risen steadily for the past 50 years, scientific advances appear to have begun to turn the tide. According to the National Center for Health Statistics, 2003 was the first year since 1930 in annual cancer deaths declined-the start of what researchers hope will be a long-term decline in cancer mortality.
The cost of cancer to the healthcare system is significant. The National Institute of Health (NIH) estimates that the overall cost of cancer in 2010 was $124 billion, with the highest costs associated with breast cancer ($16.5 billion), followed by colorectal cancer ($14 billion), lymphoma ($12 billion), lung cancer ($12 billion) and prostate cancer ($12 billion).
Cancer Immunotherapy is a Breakthrough Approach in Advancing Care
Interest in using the patient’s own immune system (i.e., nature’s own defense system against foreign or harmful germs), for the treatment of cancer dates back more than a century, when immunologist Paul Ehrlich (1900) first proposed the use of targeted antibodies as “magic bullets” against malignant tumors. However, recent advances in immunology and vaccine technology in the last decade has finally advanced the field towards making this vision a reality for patients. The first FDA approval of a cancer vaccine, Provenge® (sipuleucel‐T) for prostate cancer in 2010 and Yervoy™ (ipilimumab) for melanoma in 2011, has sparked significant scientific interest and commercial investment in cancer immunotherapy development.
A cancer vaccine (cancer immunotherapy) is designed to target and therapeutically fight cancer cells. The vaccine could contain cells, parts of cells or pure antigens. There is also broad variability of potential vectors for delivering the “vaccine”. The goal of the vaccine is to increase the immune response against cancer cells that are already present in the body. Cancer immunotherapy is considered active immunotherapy because substances injected into the body are meant to trigger the patient’s immune system to respond.
Ideally, the vaccine is specific and should only affect the cancer cells and not attack normal cells. Cancer immunotherapy causes the immune system to make antibodies to one or several specific antigens, and/or make killer T cells to attack cancer cells that express those antigens. Similar to prophylactic vaccines, cancer immunotherapy can be delivered with adjuvants which are designed to boost the immune response.
Immunotherapy is a form of therapy that uses the patient’s own immune system to fight disease. This type of treatment works in two ways: education and stimulation of the immune system to work smarter, or the introduction of additional immune system components that help the immune system work more effectively. The first is generally known as active immunotherapy and the latter is generally known as passive immunotherapy.
Cancer cells contain both self-antigens which the immune system is trained to ignore, as well as “foreign” antigens specific to cancer cells. The ideal cancer antigen is one which is highly expressed in cancer cells but not expressed on normal cells, and very “antigenic”, or provokes a strong immune response. These cells can also undergo changes where the foreign antigens are eliminated from its surface thereby eliminating the chance that the immune system will recognize and attack those tumor cells. Cancer vaccines are different than vaccines that work against viruses such as Hepatitis B in that viral vaccines work to prevent disease and cancer vaccines work to both eliminate a disease already in existence as well as prevent the recurrence of cancer once it has been detected and eliminated by standard treatments.
Cancer vaccines may contain parts of tumors, antigens, or other parts of cells, rendering them specific in their action against cancer cells in contrast to traditional chemotherapy which is a general approach that targets all growing cells The immune system can be trained to respond to specific antigens that it either did not recognize before vaccination, or the response of the previous recognition was not strong enough to prevent the onset of the diseased state. Because the immune system is equipped with special memory cells, it is the hope that this memory after immunization will prevent the cancer from recurring by the on-going immune surveillance.
FIGURE 1: Immunity and Cancer–Cancer vaccine treatment seeks to stimulate or modulate the immune system to fight disease
The immune surveillance hypothesis states that the immune system is able to recognize antigens on cells that undergo malignant transformation and can eliminate these early tumor cells; however at some point, the cells are able to escape detection by the immune system at which point tumors can become established and progress. The use of a cancer vaccine may stimulate immune system to make antibodies to one or several specific antigens, and/or make killer T cells to attack cancer cells that express those antigens.
Cancer Immunotherapy
What is cancer immunotherapy?
The immunotherapy of cancer aims at specifically activating cells of the immune system, especially the so-called cytotoxic T-cells (“killer T-cells”) to seek out and eliminate tumor cells while not harming healthy tissue.
What is NeuVax™ (nelipepimut-S or E75) and how does it work?
NeuVax works by turning on the immune system. NeuVax recruits the main components of the cellular immune system to fight cancer by presentation of a T-cell peptide epitope in the context of the peptide-HLA-T-cell receptor complex. When NeuVax is administered, the E75 peptide, a well established T-cell epitope discovered on HER2, binds to the HLA-A2 and HLA-A3 molecules on the surface of tumor cells and Antigen Presenting Cells (APCs). The peptide sends a signal to the immune system by binding in the HLA-peptide-T-cell receptor complex. Circulating T-cells recognize the peptide bound to HLA though T-cell receptors (TCRs) on their surfaces and the T-cells become “educated” and “activated” to target HER2-expressing tumor cells exhibiting the E75 epitope bound to HLA. Furthermore, activation of these T-cells leads to clonal expansion and proliferation of E75-specific “killer T-cells” that circulate through the body, identify and destroy cancer cells that are processing HER2.
Mechanism of Action: Active Specific Immunotherapy (ASI)
Tumor cells are differentiated from healthy cells by the expression of tumor-associated proteins, also known as “tumor antigens.” HER2/neu is a well established tumor-associated antigen found at various expression levels on the membrane surface of many types of human cancer cells. The human immune system is constantly surveying the body for foreign invaders (foreign proteins) or abnormal self proteins. To aid in this immune surveillance, cellular proteins such as HER2/neu and others are routinely digested or broken down inside the cell into short fragments called peptides and the small peptides are then “displayed” on the cell surface as a means of communicating with the immune system. Differences between the pool of peptides from a tumor cell and a normal cell are revealed on the outside of the cell. Peptides that are presented on or from tumor cells, but that are absent (or present to a far lesser extent) on healthy cells are called tumor-associated peptides (TAPs).
Unlike existing monoclonal antibody therapy which requires frequent, ongoing, intravenous (I.V.) infusion, NeuVax can produce continuing activation of the immune system and therapeutic levels of Killer T-cells with a once monthly intradermal (under the skin) dosing schedule that is less expensive and more convenient for both the patient and physician.
What’s the status of NeuVax™ (nelipepimut-S or E75)?
NeuVax is currently undergoing clinical testing for the adjuvant (after-surgery) treatment of early-stage HER2/neu-expressing breast and prostate cancer. NeuVax may also be developed to treat other types of solid tumors.
Patient enrollment has been initiated for the PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low-to-Intermediate HER2 Expression with NeuVax Treatment) Phase 3 clinical trial of NeuVax under the FDA approved Special Protocol Assessment to prove the safety and efficacy of the product and prepare it for market. Galena will seek FDA approval of NeuVax for the adjuvant treatment of node-positive breast cancer in women with low to intermediate levels of HER2/neu expression. Patients and investigators can visit www.NeuVax.com or ClinicalTrials.gov (identifier: NCT01479244) for more information.