Therapies that recruit and reactivate a patient’s own immune system against cancer have shown a great deal of promise. However, not all patients benefit from these therapies. Thus, developing strategies to boost immune-based treatments is critical. One approach is to develop drugs that improve the function of immune cells. This can be done by targeting transcription factors, which are proteins that help regulate the expression of other proteins. However, transcription factors are very difficult to drug because they often do not have suitable binding sites for chemical compounds. Nevertheless, we recently developed compounds that target a transcription factor known to be important in certain immune cells. Our major goal is to see if targeting this transcription factor can boost the immune response against tumors in mice. We will also try to understand how these compounds reprogram immune cells. This is important because several companies are developing similar drugs, but how these drugs work is not fully understood. The experiments in this proposal will shed light on how this class of drugs work. This will be useful for evaluating how they are used in patients to improve patient outcomes like increased survival.
Funded by the Stuart Scott Memorial Cancer Research Fund and the V Foundation Wine Celebration for Julie Maples, in honor of Antrese Rose Allegro
Breast cancer is one of the most diagnosed cancers in women and it is the top cause of cancer death in Black and Hispanic women. While great advances have been made in the detection and treatment of breast cancers, certain forms of breast cancer remain difficult to treat. Some patients develop resistance to current therapies leading to relapse, metastases, and ultimately death.
We are proposing to use our own immune cells to treat difficult cases of breast cancer. Our approach is to modify T cells with synthetic receptors to specifically recognize and kill breast cancer cells without harming normal tissues and organs.
We are using the T cells ability to patrol our body and modifying them to recognize specific molecular signals, such as the amount of a protein (HER2) present on the surface of cancer cells, to execute potent killing responses. If successful, our approach will lay the foundation for clinical studies, potentially will have major impact on our ability to treat effectively and safely some of the most difficult forms of breast cancer and will provide new approaches to other challenging solid cancers.
Immunotherapy is a new method of cancer treatment that boosts the immune system to help kill cancer cells. Patients with head and neck cancer that has returned or spread to other parts of the body have few treatment options, and immunotherapy has been a breakthrough to improved survival. However, this therapy works in less than 20% of patients. We believe that this immune system treatment does not work in some patients because their immune system is desensitized to the cancer, and the cancer is able to hide from the immune system. In this study we propose that splicing, which are gene rearrangements, can (1) help identify which patients will benefit from this treatment, and (2) find new ways to make this treatment effective for more patients. First, we will look at splicing as a marker to help predict which patients will respond to immunotherapy. Next, we will use a mouse model of oral cancer to understand how splicing is related to a suppressed immune system to understand why some patients do not respond to treatment. Lastly, we will combine immunotherapy with new drugs that can increase splicing rearrangements to see if this combination will improve response to treatment. Ultimately, we believe that study of these gene rearrangements will lead to new treatments that could help cure more patients with head and neck cancer.
The overall goal of “Enhancing Lung Cancer Screening For Eligible Patients (ELFE) through human- centered intervention” is to increase the completion rates of lung cancer screening (LCS) among eligible patients. LCS is important because it can facilitate the detection of lung cancer at the earliest and most treatable stage before the cancer has spread. The goal of ELFE is two-fold: 1) interviewing patients who have completed lung cancer screening to better understand factors that served as barriers to or facilitators of LCS participation and 2) develop a clinical intervention incorporating the lessons discovered through the interviews. We will explore the use of a Pre-Visit Planner in which a licensed medical assistant will engage with patients alone or coupled with a web portal to identify patients who are eligible for LCS. ELFE is a collaboration that includes the UC Davis Comprehensive Cancer Center, UC Davis Health, and Amazon Web Services to bring innovative research and tools to patients. Using a patient-centered intervention such as what we are proposing potentially could impact clinical practice thus, reducing the mortality associated with lung cancer.
Funded by the Scott Hamilton CARES Foundation in partnership with the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of childhood cancer mortality. Two types of these brain tumors, both with mutations in different parts of the histone 3 protein, are both aggressive and deadly. Although these tumors are so awful for the child that has one in their brain, when the tumor is removed with surgery, it is very hard to grow in a dish. For this reason, many scientists take these patient tumor cells and grow them in a mouse. Yet, we and others have seen that although this way of growing the tumors is better than nothing as it allows us to research the tumor cells, the tumor changes a lot in the mouse brain. For this reason, we have generated new models, using transplantation to a cortical organoid. A cortical organoid is a three-dimensional model of the developing human brain made from stem cells. Our work shows this system mimics more aspects of the original tumor, and also provides an opportunity to see how the tumor cells interact with the human brain. We will further optimize this system to study these pediatric brain tumor and we will now begin to ask, which cell types actually cause the tumor to recur after surgery? Which cell types are most invasive, and thus most dangers? Finally, we will also try to identify the cause of these tumors so that we can either prevent them from emerging in children in the first place, or detect them early to prevent tumor progression.
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.
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