State: New York

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women. The primary cause of death is metastasis, or spread of the cancer via the blood stream to other organs, which is incurable and associated with an average life expectancy of only 3 years. Although breast cancer death rates have declined due to screening and more effective treatments, more accurately identifying metastatic risk in order to prevent overtreatment remains a major clinical challenge. Therefore, the most important problems in breast cancer include reducing overtreatment by identifying more accurate prognostic markers and preventing spread of cancer cells in those at risk. Our program has focused on addressing these problems by studying breast cancer cell dissemination at single cell resolution using innovative experimental methods, with a focus on translating these discoveries into the clinic through multidisciplinary collaboration. In aim 1, we will confirm the association of 2 specific breast cancer tests that may more accurately identify who is at risk for recurrence, one of which identifies microscopic structures (which we call “TMEM”) that seed tumor cells into the blood and other organs. In aim 2, we will test a new drug which blocks TMEM function to see if it can block seeding of tumor cells into the blood. The project is therefore studies an entirely new approach to cancer diagnostics and treatment. The basic science studies that led to this work have been described in an award winning video entitled “Spying on Breast Cancer Metastasis” (https://www.youtube.com/watch?v=q_JDp-VePAs)

Over the past decade, harnessing the power of a patient’s own immune system for the treatment of cancer has been a major medical breakthrough. By using drugs to block inhibitory signals on immune cells, these medicines help “release the brakes” allowing them to kill cancer cells.  Given the tremendous success of this approach, our lab has worked to identify another class of drugs that help “wake up” the immune system to help it fight off cancer. We have performed extensive studies on a protein called CD40, which is naturally used by the immune system to fight off infections. By activating CD40, cells of the immune system are better able to recognize and kill cancer cells.  We modified a class of drugs, called antibodies, to help stimulate CD40 on immune cells. By doing this, we generated a drug which was twenty-five times more potent than the currently available form. This enhancement led to better immune system activation and treatment of cancer. We are now aiming to test this improved immune therapy in patients with cancer, hoping to provide another class of drugs that help the immune system attack and kill cancer cells. ​

Pancreatic cancer remains a lethal illness with limited treatment options. While harnessing the immune system has demonstrated dramatic results in controlling other cancers, it has so far failed in pancreas cancer. The development of effective immunotherapy for pancreatic cancer requires the activation and expansion of immune cells that recognize and kill the cancer. We have developed a cancer vaccine by fusing malignant cells with powerful immune stimulating cells known as dendritic cells that are capable of inducing anti-tumor immunity. This strategy allows the immune system to see cancer antigens so that they can be recognized and attacked. This vaccine showed excellent results in clinical trials in patients with blood cancers. One challenge to developing a vaccine for pancreatic cancer involves obtaining adequate tumor tissue needed to create a personalize vaccine. We have solved this problem by developing a culture system that allows for growth of a patient’s tumor tissue in vitro known as organoids that can subsequently be fused with patient’s own dendritic cells created personalize vaccine. In our first aim, we will conduct a clinical trial in patients with pancreatic cancer to show the feasibility, safety, ability to stimulate a immune response and preliminary efficacy of the vaccine product. While we expect that this strategy will be feasible and work in some patients, it is likely that it will not be enough for all patients. For that reason, in the second aim, we will work with mouse models to combine the vaccine with strategies that could make it better.