Innovative Research Grants 2017
SU2C's newest Innovative Research Grant recipients were announced at the 2017 Annual Meeting of the American Association for Cancer Research (AACR), SU2C’s Scientific Partner. Awards were given to 10 early-career scientists, in a program funded by a grant from Bristol-Myers Squibb Company (BMS), an SU2C Visionary Supporter.
IRG Recipients at a Glance
Harnessing Dipeptidyl Peptidase Inhibition for Cancer Immunotherapy
Cancer immunotherapy, in which a patient’s own immune system is harnessed to destroy cancer cells, is a revolutionary new approach for combating cancer. However, many cancers are not yet amenable to immunotherapy. Even for cancers for which immunotherapies exist, only a fraction of patients respond to such treatments. Additional research is therefore needed to identify new treatment options that target novel and/or complementary mechanisms of action. One particularly intriguing yet poorly understood small molecule drug, called Val-boroPro, has been shown to be an immune-stimulating agent with striking anti-cancer activity. However, significant toxicity concerns have so far impeded further clinical advancement. The mechanistic basis of Val-boroPro’s toxicity, and whether this toxicity can be separated from its promising anti-cancer efficacy, is not yet known. Dr. Bachovchin will address this question by determining the mechanisms of action of the drug to understand both why it is effective and why it is toxic so that only the anti-cancer mechanism can be exploited in future drug design. Using such drugs, this proposal aims to identify novel mechanisms to stimulate the patient’s immune system to eradicate cancer cells. This approach is unique in that it is distinct from the vast majority of ongoing studies that are focused on modifying or optimizing currently available immunotherapies. If successful, the proposed strategies could be rapidly translated into the clinic, where it will represent an entirely new mechanism for activating the immune system to kill cancer.
Rescuing T Cell Function for Immunotherapy of Pediatric Malignancies
CAR T cell therapy is very effective in pediatric leukemia and has yielded remission rates of more than 90 percent for children with relapsed acute lymphoblastic leukemia (ALL) in early stage clinical trials. However, there remain a significant number of patients eligible for this treatment for whom a CAR T product cannot be made. Dr. Barrett, through his experience with the pediatric CAR T cell program at Children’s Hospital of Philadelphia, has discovered that the main reason for this is the poor function of T cells from the patient—they are either defective or dead. Initial studies in the Barrett lab have shown that T cells from these patients have altered metabolic states. These metabolic alterations can be induced by chemotherapy but may also exist as part of the influence of particular types of cancer. Dr. Barrett seeks to identify the specific nature of these metabolic alterations in order to devise ways to reverse them, hence eventually enabling effective CAR T cells to be made. Additionally, the effect of chemotherapy on the metabolic status of T cells will be investigated in order to define therapeutic interventions to maintain T cell efficacy for immunotherapy in the face of chemotherapy. This innovative approach to understanding how to enhance CAR T-cell production should shed urgently needed light on the process of CAR T-cell generation.
Targeting the Pro-metastatic Niche in the Liver for Cancer Immunotherapy
Metastasis to the liver is a major cause of morbidity and mortality associated with a wide range of cancers, including gastrointestinal (GI) malignancies such as pancreatic ductal adenocarcinoma (PDAC). Immunotherapy, whose aim is to harness the body’s own immune system to fight cancer, has recently demonstrated considerable efficacy for patients with a variety of types of cancer, including patients with metastatic disease. However, outcomes vary tremendously among different patients and often do not last very long. In gastrointestinal malignancies, for instance, metastasis to the liver is common and associated with poor responsiveness to immunotherapy. In pancreatic cancer, which is predicted to become the second leading cause of cancer-related deaths by 2030, the liver is directly exposed via the portal vein to soluble factors and antigens released by developing tumors. Preliminary work from the Beatty lab has found that the immune microenvironment in the liver is conditioned early during pancreatic cancer development. This results in a liver that displays enhanced susceptibility to metastasis. Based on these findings, Dr. Beatty has developed the hypothesis that the immune microenvironment in the liver is inherently malleable; it has the capacity to support or suppress anti-tumor immunity. During cancer development, the microenvironment is induced to favor cancer cell metastasis and limit the efficacy of cancer immunotherapy. With this grant, Dr. Beatty will test this idea, and try to better understand the exact mechanism by which the liver may regulate efficacy to immunotherapy. By delineating the underlying mechanisms that generate a “pro-metastatic,” immunotherapy–resistant immune microenvironment within the liver, this work has the potential to provide novel opportunities for clinical intervention and to impact the lives of many patients.
T Cell Immunotherapy for Core Binding Factor Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a frequently fatal blood cancer with a number of different subtypes, many of which have characteristic abnormalities in certain genes and proteins. “Core Binding Factor (CBF)” AML is a type of AML that is named after the gene rearrangements that are characteristic of the subtype. CBF AML is relatively common in younger patients and although it has a better prognosis than some other types of AML, incomplete response to chemotherapy and/or relapse still often occurs, resulting in the death of many patients. The past few years have seen the development of several new and exciting types immunotherapy, including infusions of a category of immune cells called T cells that can be engineered to recognize and kill cancer cells. Unfortunately, most of the T cell immunotherapies available today are not suitable for AML because the proteins on the surface of cancerous AML cells are similar to the proteins on the surface of normal blood and bone marrow cells, leading to severe side effects when T cell immunotherapy also targets these normal cells. To address this issue, Dr. Bleakley aims to develop immunotherapy that targets abnormal cancer-specific proteins inside the cell rather than less-specific proteins on the cell surface. This strategy is based on her laboratory’s recent findings that certain parts of the abnormal proteins made in CBF AML can be recognized by T cells of normal, healthy people. The ultimate goal of this study is to harness the discoveries from this project to develop innovative T cell immunotherapies and therapeutic vaccine candidates for preclinical and, ultimately, clinical testing.
Imaging CAR T Cells with a Dual Function PET Reporter Gene
Immunotherapy has brought a sea change to how cancers are treated, with the potential for complete recovery from cancers with otherwise low survival rates. Among those therapies, CAR T cell therapy has shown dramatic activity in several hematological cancers, including advanced, chemotherapy-resistant acute lymphoblastic leukemia. In CAR T cells, a type of white blood cell called T cells that scan the bloodstream for cellular abnormalities and infections have been engineered with chimeric antigen receptors (CARs) that target tumor-associated antigens. These CAR T cells have shown activity in a number of hematological cancers, however a major obstacle in the development of CAR T cells that target solid tumors is the difficulty in determining the treatment efficacy and related toxicity because the fate of the therapeutically administered cells cannot be assessed directly. To address these issues, in vivo cell-tracking methods are critically needed to monitor noninvasively the fate of the administered cells in the body. To achieve this goal, Dr. Farwell proposes to develop a novel traceable genetic system that carries a potent “suicide gene.” With such a system, the fate of T cells will be monitored via a radiotracer using positron emission tomography (PET). Furthermore, the suicide gene function can be activated if the engineered T cells need to be destroyed because of undesirable and/or toxic effects. By developing such a tool, Dr. Farwell and his team have the potential to create a platform that opens the door to numerous imaging applications that will find widespread use in CAR T cell therapy and other cell-based therapies.
Identifying and Targeting Mechanisms of Resistance to Immunotherapy
A form of immunotherapy called immune checkpoint blockade therapy has revolutionized the treatment of metastatic melanoma. However, not all patients respond to this kind of therapy, and some who respond initially will later have progression in their disease. Understanding the mechanism of these varied responses could improve patient care for two reasons. First, patients who are more likely to respond favorably to the treatment could be identified before embarking on a treatment. Second, novel drug targets could be identified that have the potential to overcome resistance to the therapy. By analyzing samples from melanoma patients treated with immunotherapies, Dr. Haq and his team uncovered mutations in genes associated with treatment outcome. In some non-responding patients, mutations that hindered the ability of the patient’s immune system to destroy tumor cells led to treatment resistance. In other cases, mutations in genes without known function were identified that predicted beneficial response to immunotherapies. To understand better the role of genes associated with resistance or response to immunotherapy, Dr. Haq will use a unique tool developed in his lab to recreate resistance mutations in a mouse model. This platform will also be used to evaluate whether a drug currently in clinical trials can overcome immunotherapy resistance. Altogether, this approach could transform the way we understand and treat resistance to immunotherapy.
Reworking Negative Receptor Signals for Improved Anti-glioma T-cell Therapy
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. Currently, the outlook for patients with GBM is poor: the five-year survival rate is less than 5 percent. Effective new therapies are urgently needed. Dr. Hegde and her team have utilized recent advances in cancer immunotherapy to generate chimeric antigen receptor (CAR) T-cells that specifically recognize the human epidermal growth factor receptor 2 (HER2), a protein that is specifically associated with GBM. A phase I trial conducted by Dr. Hegde showed that HER2-CAR T cells presented no treatment-related toxicities, and offered clinical benefit to 50 percent of the patients treated. Thus, while HER2-CAR T cells have high therapeutic potential, there is a clear need to improve their anti-GBM activity. In this project, a sophisticated methodology developed by Dr. Hegde and her lab will enable the development of T-cells able to kill GBM cells expressing HER2, and overcome/reverse the immune-inhibition of the tumor, with minimal toxicity. This study bears the potential to dramatically improve outcomes for GBM patients, and advance information leading to future standards in brain tumor immunotherapy.
Potentiating Novel Engineered Cellular Therapies for Solid Tumors
Glioblastoma multiforme (GBM), the most common malignant brain tumor, has a dismal prognosis, with median survival of only 12 to 15 months. Development of novel and targeted therapies are therefore critical to treat this devastating disease. Recent studies have raised hopes that immunotherapy, whose aim is to harness the body’s own immune system to fight cancer, and has recently established itself as a proven therapy for primarily leukemia and lymphomas, may be able to reverse this trend. In a recent clinical trial lead by Dr. Maus and her lab, one form of immunotherapy called Chimeric Antigen Receptor (CAR)-T cell treatment, was indeed successfully used to target cells containing a specific mutation present in 20-30% of patients with GBM. These engineered T-cells successfully trafficked to the brain and eliminated tumor cells with minimal toxicity. Based on this very promising preliminary work, Dr. Maus and her lab are now proposing to develop a second generation of CAR-T cells that target cancer cells with the specific mutation, and also modulate the immunosuppressive tumor microenvironment to maximize the efficacy of treatment in mouse animal models. The ultimate goal of this study is to engineer powerful T cells, resulting in a new form of potentially curative treatment for brain tumors. Furthermore, in addition to treating brain tumors, this technology has the potential to be applied as a therapy for other forms of cancer.
Delineating the Role of the Microbiome in Modulating Tumor and Host Immunity
In recent years, tremendous progress has been made in the treatment of melanoma and other cancers using immunotherapy, affording robust treatment choices for patients previously thought to have “untreatable” disease. However, a significant proportion of patients do not respond to these treatments, and there is a critical need to identify new strategies to enhance therapeutic responses. An area of study that warrants further exploration is the microbiome, the many different types of bacteria present in the human gut. There is now mounting evidence that the diversity of bacteria within the gut may affect responses to immunotherapy. In preliminary studies, Dr. Wargo and her team demonstrated that there was a direct correlation between the type of bacteria in the gut of patients with metastatic melanoma and their ability to respond to immunotherapy. Further, these differences were associated with differences in the population of immune cells in the patient’s tumors. To gain a better understanding of the mechanisms by which the gut microbiome may modulate immune responses to a range of immunotherapy, this project will explore the differences in the microbiome of patients that do and do not respond to such treatment, and devise strategies to change the microbiome to enhance the patient’s responsiveness to treatment. It is anticipated that results from these studies have the potential to lead to clinical trials incorporating strategies to enhance responses to immunotherapy (via modulation of the microbiome) for melanoma patients. It is also possible that those studies could be extended to other tumor types.
Reprogramming Tumor Immunogenicity with STING-Activating Nanoparticles
Cancer immunotherapy seeks to harness a patient’s own immune system to specifically destroy cancer cells throughout the body with minimal toxicity to surrounding tissue, while also training the immune system to “remember” how to kill cancer cells if they return. Recently approved checkpoint inhibitors have transformed the treatment of an increasing number of different types of cancer by reactivating T cells that recognize cancer cells. However, many patients still do not completely respond to this type of treatment. There are two primary and intertwined reasons for this: 1) patients have nonimmunogenic or “cold” tumors that are able to evade recognition by T cells, and 2) patients lack a sufficient number of the correct type of anti-tumor T cells necessary to efficiently destroy tumors. The aim of this research is to develop a safe and effective approach for increasing anti-tumor T cell responses within tumors and, by doing so, improve the effectiveness of checkpoint blockade immunotherapy. To achieve this goal, Dr. Wilson plans to develop “smart” nanoparticles coated with a small molecule that will act on the inflammatory pathway to turn “cold” tumors into “hot” ones, becoming recognizable by the immune system. Another complementary aspect of this project is to coat the nanoparticles with tumor antigens as well to better train T cells to recognize and attack cancer cells. Overall, this innovative proposal combines multiple approaches, using state-of-the art bioengineering, mouse tumor models, and a series of advanced proteomics and cell biology tools, and offers the potential to positively impact patient outcomes by developing a versatile, safe, and scalable drug-delivery platform for personalized immunotherapy.
Meet the Innovative Research Grants 2017 Recipients
- Reprogramming Tumor Immunogenicity with STING-Activating Nanoparticles
- Delineating the Role of the Microbiome in Modulating Tumor and Host Immunity
- Potentiating Novel Engineered Cellular Therapies for Solid Tumors
- Reworking Negative Receptor Signals for Improved Anti-glioma T-cell Therapy
- Identifying and Targeting Mechanisms of Resistance to Immunotherapy
- Imaging CAR T Cells with a Dual Function PET Reporter Gene
- T Cell Immunotherapy for Core Binding Factor Acute Myeloid Leukemia
- Targeting the Pro-metastatic Niche in the Liver for Cancer Immunotherapy
- Rescuing T Cell Function for Immunotherapy of Pediatric Malignancies
- Harnessing Dipeptidyl Peptidase Inhibition for Cancer Immunotherapy
- Defining the Mechanistic Connections Between Injury, Regeneration & Cancer
- Defining the Metabolic Dependencies of Tumors
- Imaging Cell-Level Heterogeneity in Solid Tumors for Personalized Treatment
- Deubiquitinating Enzymes as Novel Anticancer Targets
- Algorithmically-driven Quantitative Combination Cancer Therapy Engineering
- “Weak Links” in Cancer Proteostasis Networks as New Therapeutic Targets
- Metabolic Reprogramming Using Oncolytic Viruses to Improve Immunotherapy
- Phospholipid Messengers as Drivers of Dendritic Cell Dysfunction in Cancer
- Uncovering How Rad51 Paralog Mutations Contribute to Cancer Predisposition
- Targeting Cellular Plasticity in Individual Basal-Type Breast Cancer Cells
- An Emerging Tumor Suppressor Pathway to Human Cancer
- Modeling Ewing Tumor Initiation in Human Neural Crest Stem Cells
- Cancer Cell Specific, Self-Delivering Pro-Drugs
- Targeting MLL in Acute Myeloid Leukemia
- Targeting Genetic and Metabolic Networks in T-ALL
- Targeting Protein Quality Control for Cancer Therapy
- Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment
- Chimeric RNAs Generated by Trans-Splicing and their Implications in Cancer
- Exome Sequencing of Melanomas with Acquired Resistance to BRAF Inhibitors
- Identification and Targeting of Novel Rearrangements in High-Risk ALL
- A Systems Approach to Understanding Tumor Specific Drug Response
- Targeting Sleeping Cancer Cells
- Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells
- Developing New Therapeutic Strategies for Soft-tissue Sarcoma
- Framing Therapeutic Opportunities in Tumor-activated Gametogenic Programs
- Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia
- Targeting Inhibition of BCL6 for leukemia Stem Cell Eradication
- Identifying Solid Tumor Kinase Fusions via Exon Capture and 454 Sequencing
- Therapeutically Targeting the Epigenome in Aggressive Pediatric Cancers
- Endogenous Small Molecules that Regulate Signaling Pathways in Cancer Cells
- Genetic Approaches for Next Generation of Breast Cancer Tailored Programs
- Modulating Transcription Factor Abnormalities in Pediatric Cancer
- Noninvasive Molecular Profiling of Cancer via Tumor-Derived Microparticles
- A Transformative Technology to Capture and Drug New Cancer Targets
- Functional Oncogene Identification
- Probing EBV-LMP-1’s Transmembrane Activation Domain with Synthetic Peptide