Translational Archives - Page 9 of 30

Pratiti Bandopadhayay, MBBS, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Brain tumors are the leading cause of cancer related deaths and long term side effects in children. Treatments that are specifically directed to tumors, while sparing normal brain cells, are desperately required to increase the effectiveness of treatments and to reduce side effects. This project is focused on trying to find ways to inhibit specific mutations in a group of genes that are found across common childhood gliomas. Our hope is that our work will help us find ways to use medications that target these mutations specifically to allow precision medicine approaches.

Evan Weber, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Pediatric cancer patients have greatly benefited from advancements in CAR-T cell therapy, a cancer treatment in which a patient’s own T cells – a type of immune cell – are reprogrammed to recognize and kill cancer. CAR-T cell therapy has demonstrated remarkable clinical success and can even cure some patients; however, only 50% of those treated remain cured after 12 months. A major roadblock preventing this therapy from curing more patients is poor CAR-T cell survival. Patients with long-lived CAR-T cells are more likely to be cured than those with short-lived CAR-T cells. Therefore, there is an urgent need to develop strategies that help CAR-T cells stay in the fight against cancer.

My research project will test a new approach that helps CAR-T cells survive longer by tapping into the natural biology that helps T cells persist in the body. By forcing CAR-T cells to act more like naturally occurring long-lived T cells, we can boost their ability to survive and kill cancer. We will also determine the molecular “secret sauce” that allows some patients’ CAR-T cells to persist for longer compared to others. Collectively, this project will help advance more efficacious therapies for blood cancers and potentially other types of cancer in both children and adults, and reveal valuable information about CAR-T cell persistence that can be leveraged for future discoveries.

Leo Wang, MD, PhD & Nicholas Banovich, PhD

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.

Margot Lazow, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund with support from Hockey Fights Cancer

Brain and spine tumors are the leading cause of cancer-related death in children, adolescents, and young adults. Outcomes for pediatric and young adult patients diagnosed with high-grade gliomas (HGG) remain dismal, with 5-year overall survival tragically <10%, despite intensive surgery, radiation, and/or chemotherapy. There is therefore a critical need to develop effective, well-tolerated therapies for children and young adults with HGGs. Recent scientific discoveries have provided valuable insight into the genomics of these aggressive diseases and identified genetic changes which can serve as targets for therapy. Research has helped develop less toxic medicines, usually oral drugs, which can directly target specific genetic alterations present in the tumor to slow or stop its growth and spare healthy organs. We propose an innovative multi-arm clinical trial offering a precision medicine approach to treat children and young adults newly diagnosed with HGGs. Detailed genetic sequencing using advanced technology will be performed on tumor tissue from all patients upfront, with return of results within 3-4 weeks. Patients will then be assigned to one of several unique molecularly-targeted treatment arms based on (and directly targeting) the genetic alterations identified in their tumor. We will also collect blood samples as well as cerebrospinal fluid and/or future tumor tissue throughout the study. Genomic and immune profiling analyses will be performed on these specimens over time that, in combination with imaging and patient-survey measures, can predict early response or recurrence to treatment (“liquid biopsy” tools) and improve the understanding of why some tumors become resistant to therapy.

Chrystal Paulos, PhD & Ragini Kudchadkar, MD

Though survival for patients with advanced melanoma has improved over the last decade with the introduction of anti-PD-1 antibodies, half of patients treated with this therapy have disease that recurs. Both combination immunotherapies and single-agent anti-PD-1 antibodies are currently used to treat melanoma. However, combination therapies have higher responses but also higher toxicity rates. Currently, there are no definitive biomarkers that can predict which therapy choice is correct for metastatic melanoma patients.

This project is focused on understanding why patients are resistant to PD1-based therapies. We recently discovered that patients with more CD26 (a type of protein) found in the tumor’s immune cells are more responsive to treatment. These collective findings beg the question: What is the role of CD26 in the immune response to melanoma?

To answer this question we will study CD26 melanoma immunity using melanoma patients’ blood and tumor samples. This data will allow CD26 to be used as a biomarker in prognosis for patients treated with PD-1-based therapies, and allow for future studies for clinicians to use CD26 as a predictive biomarker to help select the appropriate treatment for a patient, i.e., combination or single-agent immunotherapy.

The role of CD26 activity in melanoma immune response will be defined by this project. Findings from this research will be the basis for future clinical trials to target CD26 in order to enhance immunity against tumors that are unresponsive to PD-1-based therapy in order to create new hope for patients with PD-1-refractory melanoma.

Haeseong Park, MD

Funded by the Stuart Scott Memorial Cancer Research Fund

Using immunotherapy to treat advanced cancer has improved the outlook of cancer treatment in many cancer types. However, most of the gastrointestinal cancers, including pancreatic adenocarcinoma, do not benefit from such advances in immunotherapy. Upon further research, we have learned that dense non-cancer cells that surround these cancers not only prevent the chemotherapy drugs from reaching the cancer cells, but also prevent the tumor-targeting immune cells that allow immunotherapy to be effective. Research from Washington University show that a molecule called IRAK4 can control such a process and make pancreatic cancer respond better to chemotherapy while allowing immunotherapy to be effective. Based on the promising data from the laboratory, we propose a clinic trial of CA-4948, a drug that inhibits IRAK4 and has shown to be safe by itself, to be added to standard chemotherapy drugs to ensure safety. Then an immunotherapy drug will be added to the combination. We plan to collect blood and tumor samples from the patients receiving the combination of CA-4948, chemotherapy, and immunotherapy, to understand how these drugs change the tumor and components of the immune system in patients. In addition, we plan to further test this combination in animal models to test additional mechanisms that can improve immunotherapy in pancreatic cancer.

Christopher Park, MD, PhD

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.

Kathryn O’Donnell, PhD

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.

David Loeb, MD, PhD

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.

Valentina Hoyos, MD

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.