Siteman Investment Program Awards $1.4 Million in Cancer Research Grants

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is pleased to announce funding for six new projects. These include research focused on breast and ovarian cancer development, chemoradiation therapy for cervical cancer, immunotherapy for leukemia, and enhancing the well-being of family caregivers of cancer hospice patients.

The projects will benefit from nearly $1.4 million in new grants awarded through the Siteman Investment Program. The goal of the grants is to support and accelerate the pace of innovation in cancer research. The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination Gala through the Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital; the Cancer Center Support Grant (CCSG) from the National Cancer Institute; the Alvin J. Siteman Cancer Research Fund; the Director’s Discovery Fund; and various philanthropic gifts via Siteman Cancer Center.

This cycle also includes two new clinical trials, with one focused on improving the efficacy of a personalized cancer vaccine for patients with glioblastoma, which is the deadliest brain tumor in adults, and another focused on evaluating the efficacy and safety of one week of radiotherapy versus three weeks for breast cancer patients, with the ultimate goal of reducing treatment time without negatively affecting patient outcomes.

The funded research projects are described below.

New Clinical Trial Mechanism

Project Title: A Pilot Study to Assess the Safety and Immunogenicity of a Neoantigen-based Personalized DNA Vaccine with Retifanlimab PD-1 Blockade Therapy in Patients with Newly Diagnosed Unmethylated Glioblastoma

Principal Investigator: Tanner Johanns, MD, PhD

Goal: To determine if adding an immune boosting agent, called a PD-1 inhibitor, to a personalized cancer vaccine improves immune responses in patients with newly diagnosed glioblastoma, the deadliest brain tumor in adults

 

Project Summary: Glioblastoma is the deadliest brain tumor in adults with limited treatment options. To date, therapies that aim to induce the patients’ own immune response to cancer cells have not been effective in glioblastoma for unclear reasons. Understanding why immune therapies are ineffective and how to overcome these barriers is the primary focus of our laboratory. To this end, we recently completed a study targeting neoantigens, proteins derived from mutations unique to each patient tumor, using a robust discovery pipeline, called pVac-Seq, developed at Washington University. Neoantigens were incorporated into a DNA vaccine platform and administered to patients after completion of radiation. Preliminary results showed successful induction of immune responses to neoantigens after vaccination with some long-term survivors. Based on these encouraging results, this present study will combine personalized neoantigen DNA vaccines with another immune boosting agent, termed a PD-1 inhibitor, which is approved for treatment in other cancers but has not been effective in glioblastoma. The goal of this study is to determine if the combination of neoantigen vaccine with PD-1 inhibition improves the immune response to vaccine-encoded neoantigens in patients with newly diagnosed glioblastoma. Additionally, neoantigen vaccination in combination with PD-1 inhibition is being explored in more immune-sensitive solid tumors, such as melanoma, with the idea that induction of a neoantigen-specific immune response from the vaccine will improve response rates to PD-1 inhibition. Therefore, in addition to PD-1 inhibition improving the efficacy of the neoantigen vaccine, it is also possible that the administration of a neoantigen vaccine improves the response to PD-1 inhibition in glioblastoma. Together, we hope this combination therapy improves outcomes for patients with glioblastoma, and that the results of this study provide the necessary justification to continue developing this promising therapy for our patients with brain tumors, where there is a critical need for novel effective treatment options. Ultimately, if effective, we hope this combination therapy will be incorporated into the standard treatment regimen for patients with glioblastoma and serve as a backbone to explore other immune therapy strategies that could further improve outcomes in this patient population.

 

 

Project Title: SWIFT RT: Ultra-hypofractionated Radiation for Node Positive Breast Cancer

Principal Investigator: Maria Thomas, MD, PhD

Goal: To compare the toxicity and efficacy of one week of radiotherapy (SWIFT RT) versus three weeks of radiotherapy (RT) given to the breast and nodes, while also evaluating patient quality of life and breast cosmesis

 

Project Summary: For women with breast cancer that has spread to their lymph nodes, treatment often includes radiation (high-energy X-rays focused on the breast and nodes to kill cancer cells that may have been left behind after surgery). This reduces the risk of cancer recurrence and improves a patient’s chance of surviving breast cancer. Traditionally, a course of breast cancer radiation required five to six weeks of daily treatments (Monday through Friday). Although each treatment takes about 15 minutes, daily appointments for six weeks can impact work, child care, quality of life and/or other obligations. Over time, shorter, more condensed courses of radiation (three weeks) have been shown to be just as effective and just as well-tolerated. When the three-week schedule was studied in patients with cancer spread to the nodes, this was also effective and well tolerated. Recently, a trial called UK FAST FORWARD found that one week of radiation is just as effective and well-tolerated, when compared to three weeks. However, in that trial, radiation was only given to the breast. Therefore, if cancer has spread to the nodes, three weeks remains standard. In this randomized trial (SWIFT RT), we will compare three weeks versus one week of radiation to the breast and nodes. Given this had excellent effectiveness and safety when given only to the breast, we expect similar results with the one-week schedule in this trial. We will also evaluate patient quality of life and collect blood samples to study toxicities from treatment, to offer even more individualized patient care in the future. If one week of radiation to the breast and nodes is found to be effective and well-tolerated, this would be a huge impact for women with breast cancer and would improve worldwide access to care by reducing the length of treatment.

 

 

Pre-R01 Mechanism
Project Title: TMEJ and BRCA1 Mutant Tumor Development

Principal Investigator: John Krais, PhD

Goal: To explore how DNA damage accumulates and is repaired in noncancer cells carrying a BRCA1 mutation and address the exciting possibility that suppressing a DNA repair pathway called polymerase theta-mediated end joining (TMEJ) could eliminate the transformation of cells into a malignant state

Project Summary: Mutations in genes encoding the DNA damage response machinery, including BRCA1 and BRCA2, lead to a significantly elevated risk of ovarian and breast cancer development for individuals inheriting a mutant gene. Inheritance of a mutation from one parent is sufficient to trigger tumor formation, despite also receiving a functional, nonmutated (wild-type) gene copy from the other parent. These high-risk individuals, usually with a family history of cancer, are in dire need of new tumor prevention approaches. The development of cancer prevention strategies is precluded by a shockingly limited understanding of the process where normal cells undergo transformation into malignant cancers. In fact, cells with one wild-type and one mutant copy of the BRCA1 or BRCA2 genes demonstrate very mild differences, even in their DNA damage response capabilities, yet are susceptible to cancer development. To address this paradox, we developed a BRCA1 mutant transgenic mouse strain and derived cells with wild-type BRCA1 or a single mutant copy to recapitulate an inherited mutation. In preliminary experiments we found a subtle accumulation of DNA damage in cells with a mutant copy of BRCA1 but revealed a startling increase in the activation of a mutagenic backup DNA repair pathway, Polymerase Theta-mediated end joining (TMEJ). These potentially transformative results raise the possibility that TMEJ is responsible for the mutations (mutagenesis) required for tumor development. In this proposal, we explore how DNA damage accumulates and is repaired in noncancer cells carrying a BRCA1 mutation and address the exciting possibility that suppressing TMEJ could eliminate the transformation of cells into a malignant state.

 

 

Project Title: Targeting SERPINB3 to Improve Both Tumor and Immune Response in Cervical Cancer

Principal Investigator: Stephanie Markovina, MD, PhD

Goal: To determine if small drug-like molecules can be designed to block the many protective effects that a certain protein called SERPINB3 has on cervical tumor cells, and whether this approach can sensitize cancer cells to chemoradiation therapy to a greater extent than normal cells to better treat the cancer while reducing the potential of treatment side effects

Project Summary: Cervical cancer is responsible for many cancer deaths worldwide. The standard treatment is a combination of radiation and chemotherapy and has not changed for decades. Only recently have new treatments that stimulate the patient’s immune response against the cancer shown promise. These drugs, called immune checkpoint inhibitors (ICIs), appear to work well for a small proportion of patients, and which patients will benefit from the addition of this treatment is unknown. Additionally, why some patients do not respond to standard chemoradiation or ICIs is also unknown. We have discovered that a protein called SERPINB3 protects tumor cells from anticancer therapy. This protein appears to protect tumor cells directly by preventing cell death when treated with chemoradiation and other drugs but also by influencing the immune cells within the tumor. Currently, there are no drugs that block the action of SERPINB3, and it is unclear if targeting SERPINB3 might also sensitize normal noncancer cells to these therapies, increasing the risk of side effects. To address these gaps in knowledge, I propose two specific goals for this project: 1) determine if small molecules can specifically inhibit the protective effect of SERPINB3 on cervical tumor cells and 2) if targeting of SERPINB3 sensitizes cancer cells to a greater extent than normal cells. To achieve these goals, we will employ novel tools we have developed to mimic conditions and treatments that are delivered to patients. Drug candidates we have identified through screening will be tested in these settings and fill the gap in knowledge about cervical cancer resistance and nominate new treatment approaches to improve survival from cervical cancer. While this proposal is focused on cervical cancer, the development of SERPINB3-targeting drugs may represent a personalized treatment approach for many patients with tumors that express SERPINB3, including lung cancer, head and neck cancer and an aggressive brain tumor called glioblastoma, extending the reach of this research to even more patients.

 

 

Project Title: Enhancing Home Hospice: Piloting a Digital Symptom Management Tool for Advanced Cancer Care

Principal Investigator: Karla Washington, PhD

Goal: To enhance the well-being of the family caregivers of cancer hospice patients by implementing and evaluating modifications to the ENVISION digital health tool and conducting a rigorous feasibility pilot study

Project Summary: Each year, nearly half a million Americans with advanced cancer elect to receive hospice services when disease-directed therapies are no longer effective and life expectancy is limited. Most of these individuals receive hospice in the community with family members and friends managing their symptoms, often with little training or preparation. Symptom management challenges are common in hospice, and they are a significant source of patient and family caregiver distress. For the past several years, our team has worked with hospice providers and care recipients to co-create a digital health tool and corresponding intervention called ENVISION (ENgagement and Visualization to Improve Symptoms In ONcologic care). The ENVISION application converts patient- and family caregiver-reported symptom and well-being indicators into simple data visualizations, which are summarized in daily scorecards that provide hospice teams with comprehensive, yet easily interpretable assessment data to guide care planning and prioritization of clinical responses. We recently conducted an evaluation of ENVISION’s digital inclusivity in preparation for a large, multisite trial. Evaluation results highlighted two modifications that, if implemented, would significantly increase ENVISION’s usability and potential benefit for diverse groups of patients and family caregivers: (1) simplifying the onboarding experience to make it easier for users with low digital literacy to log in to the application the first time and (2) providing additional training to help family caregivers assess patient symptoms, particularly in more advanced disease stages. In this application, we propose a two-year study that will allow us to implement and evaluate these modifications and conduct a rigorous feasibility pilot study. At the conclusion of the proposed research, our team will be well-positioned to pursue robust external support for a large-scale, multisite clinical trial of ENVISON, which we hypothesize will decrease family caregivers’ distress and improve management of patient symptoms in home hospice care.

 

Project Title: Epitope-edited Allogeneic CD2 CAR-T (UCART2edit) for T Cell Malignancies

Principal Investigator: Jingyu Xiang, MD, MSCI

 

Co-Principal Investigator: John DiPersio, MD, PhD

Goal: To utilize a genetic tool called CRISPR to generate more effective CAR-T cell therapy against tumor cells and to generate healthy immune cells that are resistant to CAR-T cell attacks. This would promote the killing of T-cell acute lymphoblastic leukemia (T-ALL) cells while preserving the immune system.

Project Summary: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer arising in T cells, an important component of the immune system. Patients with T-ALL who relapse have a poor prognosis, with a five-year survival rate of less than 10%. Chimeric antigen receptor T cell (CAR-T) therapy is a promising treatment that involves engineering healthy T cells to attack cancer cells. However, the marker that CAR-T cells use to recognize and kill T-ALL is also expressed on themselves and other healthy immune cells. This causes CAR-T cells to attack each other (fratricide) or healthy immune cells, which leads to poor CAR-T function and immunodeficiency. In this study, we will develop a novel CAR-T therapy that targets CD2, a surface marker expressed on both T-ALL and healthy T cells. To prevent CAR-T cells from killing themselves and instead focusing on attacking cancer cells, we will use a genetic tool called CRISPR to mask the CD2 marker on CAR-T cells, so they are not recognizable by the CAR-T cells. By applying this genetic tool to hematopoietic stem cells, which give rise to all the cells in the blood, we can generate healthy immune cells that are resistant to unwanted killing by CAR-T cells, therefore preserving the immune system. We hope this novel immunotherapeutic approach will thus promote T-ALL killing while preserving a healthy immune system.