Funded by the Dick Vitale Pediatric Cancer Research Fund
Acute myeloid leukemia (AML) in children is difficult to treat, and thus it is important to identify new and less toxic therapies. We have identified a protein called CD97 that is present on AML cells and is required for their maintenance. Because CD97 is present in multiple forms, we will determine which are required in AML cells. We also will make and test the ability of antibodies we have made against CD97 to eliminate AML cells. We expect our studies will not only reveal the role of CD97 in the development of childhood AML, but identify a potential new drug that may be used to treat kids with AML.
Lung cancer is a deadly disease. One common cancer treatment called immunotherapy boosts the body’s natural defenses to fight the tumor. However, while some lung cancer patients respond well to immunotherapy treatments, other patients do not respond to the therapy. This suggests that we need to find new ways to improve these treatments. Our research supported by the V Foundation aims to improve the body’s ability to fight lung cancer. We will study mechanisms to boost the effects of immunotherapy and we will test these new approaches using cancer models. This work has the potential to improve immunotherapy and expand the use of these treatments for larger numbers of lung cancer patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Ewing sarcoma is the second most common bone tumor in children, adolescents, and young adults. Patients who are diagnosed with a tumor that has not spread are usually cured. Those who are diagnosed with metastases (the tumor has spread from its initial location) are rarely cured despite decades of clinical trials and intensifying treatment regimens aimed at improving their survival. In preliminary animal experiments, we found that a drug called DFMO, already approved by the FDA for the treatment of African Sleeping Sickness, can inhibit Ewing sarcoma metastasis. We will test the hypothesis that DFMO acts by interfering with critical metabolic pathways in tumor cells, that it is safe to combine DFMO with chemotherapy, and that the combination of DFMO and chemotherapy will work better than chemotherapy alone in prolonging the lives of mice with Ewing sarcoma. Assuming we can show that the combination of DFMO and chemotherapy is better than chemotherapy alone in our mouse model, this will provide the rationale for future clinical trials testing the effectiveness of adding DFMO to standard chemotherapy regimens for Ewing sarcoma patients.
Funded by Hooters of America, LLC
Breast cancer is the most common type of cancer in women, causing many deaths each year. When the cancer has spread in the person’s body, the available treatments have many side effects and often cannot cure the disease. Research has shown promising results using immunotherapies, which make the patient’s own immune system attack the cancer. T cells are important cells of the immune system and can be very effective at attacking and killing cancer cells. Some breast cancers have a protein called HER2 that can be used as a target for T cells to attach. We plan to take the patient’s own T-cells and train them in the laboratory to attack breast cancer cells that have HER2. This treatment has proven safe in other cancer types and should have minimal side effects. However, breast cancer tumors are made up of different kinds of cells, not just cancer cells. Thus, we also plan to arm the T-cells with extra measures to get rid of the other bad cells in the tumor, making it easier for the T cells to eliminate all of the cancer. Based on previous research, we know that when successful, results using this kind of T cell-based therapy are long lasting for patients and can even cure their disease. With the recent FDA approval of T-cell therapies for several cancers, we are confident that the proposed project has the potential to improve the lives of patients with breast cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Outcomes for children with brain cancer are poor and current therapies are harmful to normal cells in the body. New therapies that only target cancer cells are greatly needed to improve outcomes for this terrible disease. We tested the ability of a modified cold-sore virus to target and kill brain cancer while not injuring normal cells in children. Results from the clinical trial were very exciting. We found that the virus directly kills cancer cells and also stimulates a child’s own immune system to attack the tumor. From the trial, we learned that in order to achieve even greater responses from the therapy, we need to continue the immune system attack on the tumor. To achieve this goal, we will combine two therapies that work well together: the altered cold-sore virus with a unique cancer vaccine. When the cancer vaccine is given before the virus, it prepares the immune system to fight the cancer and improves the virus’ ability to kill the cancer and stimulate the immune system attack on the cancer. We plan to create the ideal cancer vaccine with the cold-sore virus in the lab and then conduct a clinical trial of the combination therapy to benefit children in great need of more effective and less-toxic treatments. We expect these exciting therapies will result in even better outcomes in children with brain cancer. Importantly, this combination therapy can be used to treat other pediatric cancers, increasing the overall potential to help children with cancer and their families.
Funded by the Constellation Gold Network Distributors
Although cancer immunotherapies are beneficial for many patients, about half of patients fail to respond to treatment or may only respond for a short time. Identifying which patients are benefitting from treatment is an important goal, as non-responders are subjected to needless treatment and deprived of potentially beneficial alternative therapies. To address this challenge, we have developed a new PET scan to identify which patients are experiencing a tumor remission rapidly after the start of treatment. We will first evaluate patients with non-Hodgkin’s lymphoma that are receiving CAR T cell therapy. If our imaging technology successfully identifies patients that are responding to treatment, we expect it could also help patients with other types of cancer that are receiving immunotherapies. Another long term goal will be to test if our imaging technology can help physicians understand if new immunotherapies in clinical trials can eliminate tumors.
Merkel cell carcinoma (MCCs) is a cancer that requires additional research. It is the most deadly skin cancer. Moreover, its incidence is rising, doubling from 2000 to 2013. Until recently, there have been no effective therapies for this disease. Immunotherapies have revolutionized the treatment of MCCs. Roughly 50% of patients respond to these treatments, called PD1 inhibitors. While this is an important advance, there are critical barriers to cure. There are no biomarkers to predict who will respond to treatment. Moreover, there are no treatments for patients who fail immunotherapy. To address this critical unmet need, we have assembled a large clinical cohort of patients with MCCs across multiple institutions. We will subject them to a number of assays designed to identify what immune cells are in each sample and what they are doing. Our goal is to identify patterns that predict who responds to therapy and why or why not. The biomarkers we discover can be immediately deployed to ensure that PD1 inhibitors are only given to patients likely to respond to them. For the rest, our studies will seek to identify novel immunotherapy drug targets. If successful, we can develop new drugs that can be used against these novel targets and test them in future clinical trials. This knowledge will be critical to improve patient care and a key advance to developing a cure for this deadly disease.
Funded by the Stuart Scott Memorial Cancer Research Fund in memory of James Ebron *
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Immune checkpoint blockade (ICB) is one type of immunotherapy that has been FDA-approved for the treatment of melanoma, bladder cancer, lung cancer, and other cancers. For some patients, ICB can lead to dramatic shrinkage of their tumors and extend their life. However, many patients do not see this benefit and some patients develop serious side effects. For most cancer patients, there is no way to predict if they will benefit from or be hurt by ICB. A test that could give doctors and patients a better understanding of the risks and benefits for ICB treatment for each individual is urgently needed. Examining the blood of patients, we discovered certain immune cells in patients who are less likely to benefit from ICB. We have found this is true for both melanoma and bladder cancer patients. We plan to examine whether these cells also matter for patients with other cancers and if there are differences in these immune cells depending upon a patient’s race. We also would like to better understand this special population of immune cells and how they may be linked to immune cells in the tumor. We hope that this will lead to the development of a safe and easy test that will provide patients better information about how ICB treatment will work for them. With this information, we hope to allow patients to feel and function better and live longer by finding a therapy that will be more likely to help and less likely to hurt them.
Immune-based medicines are effective in treating and curing subsets of patients across multiple cancers. However, approximately 80% of patients across all cancers fail to respond to immune-based medicines. This lack of clinical benefit is particularly prevalent in aggressive forms of metastatic prostate cancer (MPC) that are resistant to hormonal therapies, where few objective responses to immune-based medicines have been observed.
The immune system is comprised of cells that can both promote and suppress the growth of the cancer. Our research has revealed that the microenvironment within MPC exhibits scarcity of immune cells. Furthermore, the sparse immune cells that reside within the microenvironment of MPC promote tumor growth and progression. Therefore, there is an urgent need to develop medicines that reprogram the tumor-promoting “bad” immune cells to create a more favorable environment, so the “good” immune cells can enter the tumor and kill cancer cells. The goal of our research is to identify and develop new medicines that can achieve this “switch” in the immune system, to enhance recognition and elimination of the most aggressive forms of prostate cancer. We will test these potential medicines in both mouse models of PC in the laboratory, and in patients with the most aggressive forms of MPC enrolled in clinical trials. Collectively, the findings stemming from this proposal will lead to a deeper understanding of the immune escape mechanisms that allow MPC to spread, and advance the clinical development of novel medicines to reinvigorate the body’s immune system to eradicate MPC.
This new drug, called peptide alarm therapy (PAT), is injected directly into a tumor to stimulate immune cells to attack the tumor. This drug stimulates immune responses that people already have because of exposure to viral infections and/or vaccines. We found that, in mice, injection of this drug in combination with a PD-L1 inhibitor, a drug already approved by the FDA, eliminates tumors. This new drug can be used for different types of solid tumors and is expected to have few side effects. This is a first clinical trial of this new type of drug to determine if it is safe. This new type of drug may be effective against many different tumor types in adult or pediatric patients.
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