Translational Archives - Page 10 of 30

Gregory Friedman, MD

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.

Michael Evans, PhD

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. 

Jaehyuk Choi, MD, PhD

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.

Margaret Callahan, MD, PhD

Funded by the Stuart Scott Memorial Cancer Research Fund in memory of James Ebron *

Donate Now

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.

Akash Patnaik, MD, PhD, MMSc

Funded in honor of Tony Kozy by the Maui Hui

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.

David Masopust, PhD

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.

Adrian Krainer, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

We aim to develop a novel and effective therapy for a lethal pediatric brain cancer (diffuse midline glioma, DMG). No effective treatment for DMG currently exists. This cancer arises when a mutation appears in a gene called H3F3A, causing it to produce a toxic protein. The mutant protein makes cells grow unchecked, forming a tumor in an inaccessible brain region and eventually killing the patient. Each of our genes makes RNA—so-called messenger RNA (mRNA)—and the mRNA is then read in another part of the cell to make the protein encoded by that gene. The technology we use, called “antisense”, allows us to target the mRNA made from a gene, and either destroy it or change it. Either way, the toxic protein is no longer made, and because the tumor cells require it for growth, they stop growing and die or change into normal cells. Once our antisense drug is developed, it will be injected into the fluid surrounding the spinal cord, allowing it to reach the brain tumor. Another gene, called H3F3B, encodes the same protein as H3F3A, so our method will get rid of the defective protein but not the normal protein. Therefore, the drug should not harm normal tissues outside the tumor. We will design, test, and perfect our antisense approach using cells derived from DMG tumors, and mouse models of this brain cancer. If this project is successful, the resulting antisense drug will undergo further safety tests, in preparation for clinical trials involving DMG patients.

Shivani Srivastava, PhD

Bob Bast Translational Research Grant *

Our lab is developing treatments for human cancers by engineering immune cells called “T cells” to recognize and kill tumor cells. Engineered T cells can eradicate tumors in patients with blood cancers, like leukemia and lymphoma. However, they have had limited success so far against more common “solid tumors”, like breast and lung cancer, which are responsible for the majority of cancer deaths. Solid tumors can evade attack by inducing T cells to lose function and become “exhausted.” Strategies to preserve T cell function, thus, are needed to extend the success of engineered T cell therapy to solid tumors. Our lab has developed a mouse model of lung cancer that mimics human tumor development and patient response to therapy. In this model, T cells engineered to overexpress a gene that promotes T cell function dramatically eliminated tumors in ~50% of mice. Based partly on these results, a clinical trial is being planned to test whether these T cells are safe and effective in patients. However, our data show that tumors still progress in ~50% of mice. We will use the mouse model we developed to define why tumors progress in a subset of mice and test different combination treatments to identify regimens that improve T cell function and kill tumors most effectively. Working with Fred Hutch clinicians and industry partners, our goal is to translate the strategies that appear most effective in mouse models to the clinic to test their impact in patients.

Steven Reiner, MD

Nick Valvano Translational Research Grant *

Previously, the main treatments for cancer patients were surgery, radiation, and medicines with many unpleasant side-effects. The discovery that there are ways to turn our own defense system against cancer became a medical revolution. In some patients, this new treatment led to miracle cures that had never been seen before. The discovery was so incredible, it won a Nobel prize. Unfortunately, this new treatment does not work in as many patients as we would like. It is still a mystery why two people with the same cancer will respond differently to treatment, one patient might be cured and the other patient does not get better. This project is trying to figure out ways that will help doctors know who will be cured and who will not get better with this new treatment. We are developing a blood test to predict who will be cured before treatment begins. For those patients that are not likely to be cured, we are doing experiments to develop a medicine that can be added to the treatment in order to make the treatment cure many more patients.

Scott Hiebert, PhD

Funded by Matthew Ishbia and the Dick Vitale Pediatric Cancer Research Fund

Childhood cancers of developing muscle are some of the most difficult to treat childhood cancers. Therapy has not significantly changed in the past 20 years and there isn’t even a meaningful new treatment being considered. Currently, even after the most intensive therapy possible, a third of these tumors will return and take the life of a child or young adult. We have taken a new approach using state-of-the-art methods to identify what we hope will be more targeted and less toxic treatments that yield better outcomes. We have already identified three new therapeutic avenues that we will test. The first is to ask if the abnormal gene that drives this disease, called PAX3-FOXO1, is a good drug target. We engineered the gene to be sensitive to a derivative of a known drug. While we can’t do this in kids, it allows us to ask what would happen if we had a drug? Second, we found that PAX3-FOXO1 turns on a small number of other genes, and we already have drugs that can target some of these. Third, we identified other possible drug targets that PAX3-FOXO1 recruits. We will test if these are key to causing cancer and if they would be good drug targets. We believe that our comprehensive approach gives us the best chance in the past 30 years to change the lives of these children with cancer, and to identify drugs or drug combinations that will be less toxic and yield better outcomes for these patients.