Funded by the Dick Vitale Pediatric Cancer Research Fund
Sarcomas are cancers of connective tissues in the human body. It affects children and teenagers more than adults. Cancers that spread to other parts of the body are difficult to treat and are not often curable. A new treatment approach called immunotherapy uses the body’s own immune system to fight cancer. Our approach uses immune cells of the body, namely T cells, to find and kill tumor cells after introducing an artificial molecule called chimeric antigen receptor (CAR). These CAR-enhanced T cells developed in our laboratory recognize a protein on the surface of the cancer cell, namely HER2. Patients with advanced sarcoma received these HER2-specific CAR T cells in our ongoing clinical trial. The CAR T cells did not cause severe adverse reactions in any of the treated patients. More than half of the 10 patients who received the cell treatment benefited from it, with 2 patients achieving tumor elimination and 4 others achieving cancer stabilization. We will now test if larger dose of T cells can be tolerated or increase the chances of benefit. We will also study immune responses in these patients to identify mechanisms, if any, that can lead to improved treatments. Finally, we will evaluate a new molecule that can help CAR T cells overcome tumor signals that turns them off. The insights gained from this study will help design and develop targeted treatments for sarcoma.
Immunotherapy has revolutionized our ability to care for cancer patients, and works by enabling one’s own immune system to detect and kill cancer cells. Unfortunately, immunotherapy has not yet been broadly effective against the most common type of breast cancer, which is driven by the estrogen hormone (ER-positive or “Luminal” breast cancer). This project aims to overcome this challenge. We will investigate whether radiation treatment in combination with other targeted therapies can overcome resistance to immunotherapy in Luminal breast cancer. We will use clinically relevant breast cancer models to better understand how radiation and immunotherapy work together to stimulate anti-tumor immunity. We will use genetic tests to identify biomarkers of an effective immune response, as well as biomarkers of treatment failure. Finally, we will apply these tests to a clinical trial of radiation and immunotherapy in breast cancer patients. Our goal for this project is to determine whether radiation-immunotherapy combinations can potentially improve the lives of patients with breast cancer. We anticipate that results from this project will inform the optimal design of clinical trials investigating radiation-immunotherapy combinations in breast cancer patients.
The immune system removes transformed cells that give rise to cancer. For many years, the process that tumors use for shielding against the immune system was poorly defined. Now the factors that prevent tumors from being destroyed are being discovered. This is spurring new drugs to be made that kick-start immune cells to reject tumors. These new drugs, named immune ‘checkpoint’ inhibitors, are having a major impact on the treatment of patients with different cancers. These drugs disrupt tumor shielding to revive immune cells for combat and inspire hope that one-day patients may no longer need toxic chemotherapy. Although many patients respond well to immune therapy drugs, with time, the tumor can adapt and develop new tactics to outsmart immune cells. Now that more than 40% of cancer patients are candidates for immune therapy, drug resistance is becoming a key problem.
With colleagues at Vanderbilt University, we recently studied how resistance may develop in patients with melanoma, breast, and lung cancer. We found new factors that could cause tumor resistance, but might also be novel targets for immune therapy. In this proposal, we first plan to study these new targets in tumor samples from patients with resistance. Secondly, we will learn how they bind to tumor shielding factors and screen drugs that could block them. Finally, we will study these new immune therapy drugs in mouse models of cancer. We expect that this proof of concept study will introduce a new target for next stage development in early clinical trials.
Funded by the Stuart Scott Memorial Cancer Research Fund
Immunotherapy has been one of the most remarkable advances in our fight against cancer. Its transformative impact on patients has been recognized with the 2018 Nobel Prize in Medicine. Immunotherapy, unlike other treatments for advanced tumors, can result in long term remissions and cures. Unfortunately, only a subset of patients benefit from immunotherapy. The majority of patients experience unremitting progression of cancer and a significant number suffer serious side-effects, which are sometimes life threatening. In those patients, immunotherapy could end up delaying or preventing other useful treatments. Cancer patients and their doctors badly need tests called ‘predictive biomarkers’ to determine whether a particular patient will benefit or be harmed by immunotherapy. Here, we propose to discover such biomarkers by analyzing tumor tissue samples from a large group of patients treated with immunotherapy. We have established a database (MIRIE) which includes all University of Michigan patients who received cancer immunotherapy since 2011. We have also developed a novel molecular assay (TAGTILE) to identify gene changes and gene expression patterns in their tumor tissues obtained before immunotherapy. By using TAGTILE to compare tumors from patients who did benefit from the therapy to tumors from patients who did not, we will be able to identify molecular characteristics of responding tumors. This information will be used to create a diagnostic test (e.g. a decision chart) to help oncologists and patients decide whether to choose immunotherapy. When routinely implemented, such a test can improve results in patients and avoid unnecessary side-effects.
Lung cancer is the leading cause of cancer death in the US and worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. A subset of these cancers has a “driver” gene mutation the epidermal growth factor receptor (EGFR) for which targeted agents are highly effective in causing tumors to shrink. However, it never cures patients and the tumor always grows back. This proposal focuses on why the cancer is not completely killed even though all of the tumor cells have this mutation, and how to overcome this problem and kill the cancer more thoroughly. Our published and preliminary data have demonstrated that targeted therapy rapidly induces drug persistent cancer stem cells (DPCs) within days of starting therapy, and these DPCs don’t die with the drug. We show that this therapy specifically activates other genes called Notch3 and β-catenin that are essential for this effect. We show in animal experiments that targeting both EGFR and β-catenin result in reduced numbers of DPCs, and improved depth and duration of response and overall survival. This is a completely different approach than trying to target drug “resistance” pathways that develop months after initiation of therapy due to the “persistence” of tumor in the early days of therapy. Our goal is to eliminate tumor persistence so that it doesn’t have the chance to develop resistance, resulting in the cure of these patients. In this application, we propose to study how this persistence happens and attempt to move toward curing these patients by targeting β-catenin in combination with EGFR in a pilot human clinical trial. Successful completion of the proposed research will increase our understanding of why tumor cells are not eradicated with EGFR targeted therapy and test a novel drug combination that we hope will improve the survival of these patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Only half of children with neuroblastoma that is found to be “high-risk” (HR-NB) live after getting the best known treatments. To change this, we need to know what makes HR-NB grow, and find new targets to attack. The New Approaches to Neuroblastoma Therapy (NANT) (www.nant.org) is a team of doctors working with patients and/or in labs to find new treatment ideas and test them in children whose tumor didn’t go away after getting the best known treatments. If NANT’s new treatments are safe and make some tumors get smaller, they are then tested in more children to see if the new treatment is better than the best-known treatments. A little blood, bone marrow, and tumor are also taken from patients on NANT treatments to study in labs to see why our new idea did or didn’t work, and how we can make them better. There are 18 NANT hospitals in the United States, Canada, Australia, and Europe. NANT is the only group working only on new/better HR-NB treatments. This grant will support NANT doctors, labs, and the people who work in the NANT office to quickly take new ideas from labs and turn them into treatments being given to children with HR-NB. It also helps us to store patient samples so they can be used to keep finding new and better ideas. Our goal is to find safe treatments that will help more children with HR-NB to live.
Funded in partnership with Cannonball Kids cancer Foundation, in memory of Tyler Trent
Glioblastoma (GBM) is the most aggressive and devastating brain tumor, and it currently has no known cure. Less than 20% of young adults diagnosed with GBM survive more than 24 months. GBM can resist treatment in many ways. These include expressing an enzyme called CD73 and changing the expression of proteins on its surface. Natural killer cells are able to fight and kill GBM, however this ability is often blocked around growing GBM cells. In order to rescue the activity of these cells, we are developing new immunotherapies by genetically modifying natural killer cells to shut down ways that GBM uses to grow. We are also combining these cells with drugs that can help them travel deeper into tumors. This immunotherapy is an entirely new way to treat GBM and has significant promise, for patients, over traditional treatments.
Funded in partnership with the Goldberg Family Foundation
We need better tools to screen for and diagnose cancer earlier and at a curable stage in individuals that carry inherited mutations such as BRCA1/2 and other cancer susceptibility genes that put them at highrisk for breast, ovarian, prostate, pancreatic and other cancers. We propose to use powerful new approachesfor “next-generation” DNA sequencing from standard blood samples to identify circulating tumor DNA mutations as a very sensitive markerof early cancers in high-risk individuals. These “liquid biopsies” may prove to be a far easier and more sensitive way to screen for cancer than our current imaging based approachesusing mammograms, MRI’s, etc. To this end, we have been collecting blood samples from our genetically high-risk patients with and without cancer, and before and after prophylactic or cancer surgeries, for liquid-biopsy analyses using technology developed at Stanford.
In 2018, 81,000 people were diagnosed with bladder cancer (BC) in the US and 17,000 people died from this disease. Three of every four new cases have an early stage of disease, called non-muscle invasive bladder cancer. This type of BC is treatable, but for over half of these patients the cancer keeps coming back and so these ‘high-risk’ patients need additional treatments. Today, we do not know which patients will have their cancer return and so we need to develop a way to know in order to help them sooner. Several cancer causing chemicals are associated with BC and so to help reduce new BC cases we need to identify and remove these chemicals from our environment. A new approach is necessary to tackle BC and our group has shown that our pet dogs can help. Each year in the US, over 60,000 dogs are diagnosed with BC. In this study, our team at NCSU College of Veterinary Medicine and Duke Cancer Institute will look for shared genetic changes in canine and human BC that may provide clues to why these cancers keep returning and how to prevent them. Our dogs live with us and so we will also study whether dogs with early BC share common chemical exposures in the home. This study of canine and human BC will allow us to determine how much help our pet dogs can provide us in looking for new ways to improve BC treatment for both ourselves and for them.
African Americans have the highest percentage of new cancer cases in the United States and the worst outcomes. Other diverse populations have difficulty getting to a cancer treatment center or need help figuring out the system one they arrive. Some people die from cancers that can be prevented or treated, simply because they are not aware of all of the treatment options. Cancer care can be very difficult because many times a patient has more than one doctor who is part of their care team. This can be scary and may make some people choose not to get cancer treatment, even if they can be cured. WFBCCC wants to make sure that everyone has access to the best cancer care possible. This may include patients participating in research that may improve outcomes for them but also may help provide information that can help tailor treatments for the next generation of cancer patients. It is important to make sure all populations are represented in studies that look at new treatments or supports for cancer patients. To meet that goal, we created a population health navigator program- people who are from the community who can help people learn about cancer, how to prevent it, what screening is required and what treatments are available. If someone is diagnosed with cancer, the navigator will assist that person by helping to remove barriers to care and will talk with patients about clinical research as part of their care.
