Lung cancer is the leading cancer killer in both men and women in the U.S. Early detection is the most effective way to fight against this deadly disease. In recent years, an imaging method known as low-dose CT (LDCT) scan has been studied in people at higher risk of getting lung cancer. LDCT scans can help find nodules in the lungs that may be cancer. However, majority of those nodules are actually benign, yet exposing many of those patients to a needle biopsy or other invasive procedures. Hence, there is an urgent and unmet need for an accurate and non-invasive approach to distinguish those nodules that are malignant from those that are not. In this proposal, we will develop and validate a novel method to integrate a blood test and the LDCT imaging for the early detection of lung cancer. Specifically, from blood we extract cell-free DNA, from which we develop an ultra-sensitive assay to profiles the epigenome of cell-free DNA, therefore to detect even a trace amount of tumor DNA. Using advanced machine learning algorithms on the integrated genomics and imaging data, we aim to significantly improve the accuracy of the cancer detection. For those patients with nodules identified from LDCT, we will integrate the two sources of information to determine whether the nodules are malignant or benign.
Liver cancer is one of the deadliest cancers in the world and it is becoming more common in the United States due to liver disease or liver scarring. Patients with liver problems are at risk of developing liver cancer, and if the cancer is found at an early stage, it can be cured. Therefore, patients with liver problems should be screened regularly so that the cancer can be found early. Unfortunately, current screening techniques are not very sensitive and require trips to special imaging centers twice a year. Our work will create a new and better screening tool for early detection of liver cancer that can be used anywhere. By improving the quality and access to better imaging, screening will be more effective and can be done wherever patients need it most, without the need to travel to a hospital or specialized imaging center. We believe that by improving both the quality and access to screening, patients with liver cancer will be found at an earlier stage, allowing for better patient care. Further, easier access to this new screening tool will allow more people to access the healthcare they need.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Children with aggressive brain tumors do poorly, and outcomes haven’t gotten much better for these terrible diseases in the past thirty years. A recent new treatment called chimeric antigen receptor (CAR) T cell therapy provides hope for these patients. CAR T cell therapy takes a patient’s own immune cells and reprograms them to find and kill cancer cells. We recently opened a unique Phase I clinical trial (NCT04510051) that uses CAR T cells to help children with hard-to-treat brain tumors.
We are excited that the first few patients treated on our trial had some shrinkage of their tumors. This gives us hope that CAR T treatment can help children with these diseases. Unfortunately, responses so far have been temporary, highlighting the clear and urgent need to improve these promising therapies. Our trial lets us sample cerebrospinal fluid repeatedly during treatment. This gives us a valuable chance to study in fine detail how CAR T cells talk to the patient’s immune system, and how that conversation changes over time. We know that if CAR T cells can teach the immune system to destroy tumor cells, treatment will work better. However, this does not happen very often in patients. Our study will help us figure out how to make CAR T cells that effectively promote an antitumor immune response, leading to better therapy for pediatric brain tumors with five years.
Parker Bridge Fellows Program; Funded in partnership between Parker Institute for Cancer Immunotherapy and the V Foundation
Cancers are driven by mutations, or changes in the DNA that encode the proteins and processes that allow the cells in our body to function normally. Those mutations make proteins work differently, making cancer cells grow faster or live longer, but they also make cancer cells look different from normal cells to the immune system. This process is similar to when someone gets a viral infection, where viruses infect normal cells, and the immune system battles the infection by recognizing the infected cells by the presence of viral proteins.
There are a series of molecules, called the Human Leukocyte Antigens (HLAs), that are responsible for showing those foreign proteins to the immune system on the surface of the diseased cells. Cancer cells can also change or lose these HLAs, so that the immune system no longer sees the cancer cells as “different” from normal cells. My research is focused in understanding these HLA molecules in skin cancer, to address the question of how the cancer cells avoid getting killed by the immune system. Skin cancers are generally treated with therapies that help the immune system kill cancer cells, and my research helps us understand why these therapies may or may not work. By explaining whether HLAs are different in cancer cells, my research may improve the success of our treatment strategies in skin cancer.
Parker Bridge Fellows Program; Funded in partnership between Parker Institute for Cancer Immunotherapy and the V Foundation
Cancer immunotherapy holds great promise to treat cancers since it boosts the human body’s own immune system to eradicate cancers. Cytotoxic T cells are the central arsenal in our immune system to find and attack cancer cells without harming the healthy cells. These T cells harbor a high diversity of T cell receptors (TCR) to specifically recognize tumor neoantigens, which are proteins arising from mutations in cancers but not in normal cells. Neoantigens are highly unique in each patient. Therefore, it is essential to identify tumor neoantigens and paired TCRs in each patient to develop personalized cancer immunotherapies such as tumor neoantigen vaccines and TCR-engineered T cell adoptive therapy. Here we will develop an innovative platform to map neoantigen specificity, TCR repertoire and molecular phenotype of T cells at the single-cell level. This platform will permit a rapid, low-cost, and high-throughput mapping of patient-specific neoantigens, allowing cancer immunotherapy more accessible to each patient. Linking TCR recognition of tumor neoantigens with molecular programming of tumor-targeting T cells, we will understand how the T cells “see” neoantigens impact their cell fate decision to become highly-protective T cells that eliminate cancers or exhausted T cells that cannot work. Completion of this work will significantly facilitate the development of patient-tailored cancer immunotherapy.
Parker Bridge Fellows Program; Funded in partnership between Parker Institute for Cancer Immunotherapy and the V Foundation
Cancer remains the second leading cause of death in the US. In order to tackle cancers, a new kind of therapy has emerged, termed immunotherapy, which aims to boost the immune system’s ability to fight the cancer. However, a major fraction of patients do not respond to immunotherapies currently. If we can figure out what other roadblocks to the immune system exist in these patients, we could expand the benefits to survival and quality of life to more people.
The immune system is a complicated team, with different cell types doing different roles. In order to work together these cells must talk to each through cell signaling and have to be in the right formations to carry out a successful play against the tumor. We want to discover how this teamwork can break down and design therapies to patch those issues.
The tumor is made up of more than just immune cells of course, and our project will focus on two types of cells that talk to the immune system. One cell type is the fibroblast which makes the building materials that hold our tissues together. Another cell type is the endothelial cell which forms blood vessels which serve as the roads and highways that carry cells, nutrients, and drugs into the tumor. If we can understand how these cells break immune cell teamwork, we can reveal new weak spots to target, making immunotherapies even stronger.
New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured. Early research suggests that these powerful drugs are safe to use as part of the first or second treatment in patients with cHL and using them earlier could lead to more cures. However, we have not done the research to clarify when is the best time to use immune therapy in cHL and to determine which drugs are best to combine with immune therapy in order to cure more patients.
My research will answer important questions about the best way to use immune therapy for cHL: (1) How should we use immune therapy as part of the first treatment to cure the most patients and reduce the side effects of our standard treatments? (2) How should we use immune therapy as the second treatment in patients who are not cured by their first treatment? (3) Can we predict which patients will respond best to immune therapies to help us choose the patients most likely to benefit from these new treatments? And, in cHL patients who are resistant to immune therapy, can we reverse the resistance?
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.
Harnessing the immune system to eliminate tumor cells has led to remarkable responses in several advanced cancer types. T cells are the key immune cell type which are engineered in the lab to seek out and destroy tumor cells, however in many cases tumor cells adapt to evade T cell killing, leading to disease relapses. Advances in cell engineering now permit T cells to be made in the lab from specialized stem cells. This technology promises to provide more cancer patients access to T cell therapies, but also presents the opportunity to make T cells more effective in prevent tumor escape. The goal of this research project is to study the ways in which tumor cells evade killing by lab-grown T cells, and how engineering specific molecules on lab-grown T cells may enable us to turn on tumor killing mechanisms to prevent tumor cell escape. Our overall goal is to further the development of this new kind of T cell therapy to be more effective across a wider range of cancer patients.
Cancer treatments often fail to produce durable responses and resistant tumors eventually regrow. This process presents a major clinical challenge and results in significant patient mortality. The molecular details of this process, termed acquired resistance,are poorly understood and there are currently no therapeutic options to prevent it. For cancer immunotherapy, acquired resistance is emerging as a prevalent phenomenon affecting approximately half of patients who initially respond to treatment. Key to this process are the leftover tumor cells which remain alive and seed resistant tumors. We have observed a small subpopulation of cancer cells which survive directcytotoxic T cell attack over prolonged time periods. These cells, termed persister cells, survive through unknown mechanisms. In this proposal we will determine how persister cells survive despite undergoing T cell attackand also how a subset of persister cells eventually regrow and exhibit overt T cell resistance. If successful, our proposed work will shed light on acquired resistance to immunotherapy and may reveal new approaches to prevent tumors from recurring.
