Read about the projects funded by the Midwest Biomedical Accelerator Consortium (MBArC ) in 2021.
Tumor-Retentive Immunostimulation as Safe Combination Therapy with Immune Checkpoint Inhibitors (KU)
Solid tumors account for more than 80% of cancer-related deaths, with 18.2 M Americans projected to have had some form of cancer as of 2020. The economic burden of the disease is reflected by the national costs of care, which were estimated to be ~$158 B for 2020 alone. Current clinical solutions for solid tumors range from surgery and radiation to chemotherapy. Despite being recognized as first-line treatments, these methodologies are often compounded by myriad side effects and a lack of tumor cell killing specificity. To this end, cancer immunotherapy has emerged as a viable therapeutic option that functions by activating the body’s immune system to recognize and destroy cancer cells. The immunosuppressive environment established in solid tumors inhibits immune recognition and activation. Checkpoint inhibitors (CPIs) have been a major breakthrough in the field of cancer immunotherapy, and although CPIs exhibit unprecedented efficacy in tumor clearance, they are only effective in patients with an already ‘hot’ tumor (immunogenic). Since only 20-30% of solid tumors are considered ‘hot’, CPIs remain a viable treatment option for only a small population of patients. These therapies are often administered by IV injection, resulting in systemic exposure of immunostimulants and a limited dose of the drug reaching the tumor tissue while the majority persists in the bloodstream, causing immune related adverse events and toxicity. Systemic stimulation of the immune system could also amplify deleterious side effects of checkpoint inhibitors, for example cytokine release syndrome. The investigators aim to develop a salvage therapy for patients with palpable (injectable) solid tumors who have failed checkpoint inhibitor therapy. The envisioned product will be a small volume injectable solution of immunostimulant, that, in combination with CPIs, will have the potential to recruit and activate immune cells in the tumor microenvironment and draining lymph nodes with negligible systemic exposure, thus improving the efficacy of existing CPIs.
ImmunAdvisor: High-Throughput T Cell Receptor Discovery for Affordable Commercial Personalized Cancer Therapies (KU)
The disease burden for cancers susceptible to immunotherapy is substantial, and includes most adult cancers including lung cancer, melanoma, and kidney cancers. Over one third of drugs in development today are for cancer therapeutics, reflecting the very high unmet medical need. Estimated national expenditures for cancer care in the U.S. were ~$150 B in 2018 alone. Some of the most effective drugs for various types of cancer are immunotherapy checkpoint inhibitors, which are often used as first line therapies but show resistance with a significant portion of patients. Cell-based therapies are more expensive ($300,000-$600,000 per patient treated) but they offer more powerful treatment options that can target the cancer, and lead to lasting cures in many patients. However, current cell-based therapies are often unable to target cancer effectively without damaging healthy tissue substantially. In addressing these limitations, use of T cell receptors from the patient’s own immune response has shown success in clinical trials, but the cost and logistical issues for this approach have prevented broad clinical adoption. To directly address these urgent needs, this team of innovators proposes to develop ImmunAdvisor, a unique technological approach that will enable robust and rapid T cell receptor identification to enable broadly applicable and personalized T cell receptor cancer therapies. The proprietary approach will enable miniaturization and parallelization of all the technical steps required to enable cell-based therapies on a more rapid and low-cost scale. The high throughput TCR discovery platform will offer bespoke autologous T cell receptor identification for biopharmaceutical companies to use during patient treatment. The high-throughput process will allow simultaneous screening and analysis of multiple patients’ TCR therapeutics, thereby enabling effective delivery of personalized cancer treatment in clinical settings, with clear economic and quality of life advantages to patients, clinicians as well as payers.
Improve Cancer Immunotherapy by Targeting RNA-Binding Protein HuR (KU)
Cancer remains a huge threat to human health. In the U. S., currently, an estimated 40 out of 100 men and 39 out of 100 women are projected to develop cancer during their lifetime. Nearly 1.9 M new cancer cases were expected to be diagnosed and about 606,570 Americans were expected to die of cancer in 2021. Depending on the type and stage of the disease, various types of cancer treatments are available including surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, etc. Cancer immunotherapy with immune checkpoint inhibitors (ICIs) such as antibodies against programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), has emerged as a revolutionary treatment strategy, as recognized by the 2018 Nobel Prize in Physiology or Medicine. These therapies have been proven to be effective in many types of cancers, including melanoma and lung cancer. However, the treatment response rate in the latter is 50%. The response rate to ICI immunotherapy has been a critical determining factor for many other solid tumors as well, with most of them being at the lower end, ranging from 10-20%, hindering access to life-saving treatments for patients as well as further growth of the current $100 B annual market. It is an urgent and unmet medical need to overcome cancer immunoresistance and improve patients' response to ICI immunotherapy. The RNA-binding protein Hu antigen R (HuR) has been found to be overexpressed in most cancers – it has been shown that PD-L1 is a direct mRNA target of HuR, and related signaling pathways are responsible for tumor cell immune evasion and resistance to ICI immunotherapy. While HuR has been considered “undruggable” thus far, this team of innovators has identified new small molecules that inhibit HuR with promising anti-tumor efficacy in multiple animal tumor models. Their envisioned product is a daily oral HuR inhibitor for patients undergoing anti-PD-1/L1 immunotherapy. With the potential to be used as a maintenance therapy as well, the proposed adjuvant therapy can greatly improve treatment efficacy in combination with the current standard-of-care ICI immunotherapy, and possibly, even conventional chemo/radio/hormone therapies and surgery.
3D Printed Borate Glass-Hydrogel Dressings for Wound Healing (MS&T)
Co-Investigator: Fateme (Sha) Fayyazbakhsh
Collaborator: Delbert Day
Approximately 1% of the global burden of diseases is related to burns – it led to more than 9 M injuries and 120,000 deaths in 2017 alone. Although there has been a 50% decline in burn incidents over the last three decades in the U. S., burn wounds are still one of the most prevalent traumas and account for a significant burden on our healthcare system. According to the Center for Disease Control (CDC), 1.1 M people suffer burn injuries that require medical attention accounting for over 60% of the acute hospitalizations annually in the U. S. The global segment of advanced dressing in the burn care market is estimated to reach $480 M by 2026. The major factors contributing to the growth of the advanced burn wound dressing market are the rising demand for minimally invasive procedures and a shift toward outpatient treatment. In addition, advantages of advanced burn wound dressings such as accelerated wound healing, reduced pain, and overall cost efficiency are likely to fuel market expansion in the future. Early burn wound excision and autologous split-thickness skin grafts are the clinical gold standards for treatment of deep partial-thickness and full-thickness burns, and have significantly improved outcomes by reducing mortality rates. However, shortage in donor skin tissue, chronic graft rejection, impaired healing, infection, and scarring are major challenges in burn wound treatment. Additionally, although wet-to-dry wound dressings are the current standard of care for partial-thickness burns and for supporting grafts, most burn wounds end up with inadequate healing, poor moisture retention, pain, traumatic removal, and contractures. To address this widespread problem, the team is developing an innovative 3D printed wound dressing. This novel material is composed of natural hydrogels and borate bioactive glass (BBG), and is designed to enable long-term moisture retention resulting in faster healing of deep partial-thickness burn wounds.
Development of a Bacterial Cancer Immunotherapy for the Treatment of Pancreatic Cancer (MU)
Pancreatic cancer (PanC) will become the second most lethal cancer by 2030. In 2021 alone, it was estimated that ~57,600 people were diagnosed with PanC in the U. S. PanC is largely asymptomatic in the early stages of the diseases, and only ~20% of patients are diagnosed early enough to qualify for curative surgery (pancreatectomy). Surgery is costly, causes significant morbidity, and substantially reduces quality of life for these patients. Further, over 75% of these patients will eventually relapse with local or distant tumors suggesting that patients with seemingly local disease already have undetectable micrometastases, which underscores the inherent systemic nature of the disease. Patients presenting with distant metastatic disease are uncurable under the current standard of care. These patients are treated with chemotherapy that are considerably toxic and yet, lack durable survival benefit. Most patients quickly develop chemoresistance and die within a year of treatment initiation. Agents that enable host immune cells to recognize and kill cancer cells (immunotherapy) have demonstrated impressive durable benefits in several other systemic cancers, but this treatment modality is efficacious in only 1% of PanC patients with well-defined tumor genetic features, further limiting treatment options for this disease. This lack of immunotherapy efficacy is due to the paucity of robust immune-stimulating tumor antigen on PanC cells, the dense fibrous stroma around PanC that limit penetration of immune cells, and the immune suppressive nature of the PanC microenvironment. Thus, targeted therapies have worked in lung and skin cancers, but failed in PanC. Targeting the unique biology of PanC, rather than individual molecules, may reveal novel therapeutic opportunities that are different from the toxic and inefficacious standard of care interventions. This team of innovators is proposing a well-tolerated anti-cancer biologic that has the potential to target and eliminate PanC, including distant metastases. The biologic will generate systemic tumor immunity to achieve durable clinical benefits for patients, and will be targeted to all PanC patients, irrespective of disease stage. Patients will receive acute intravenous bolus injections (supplied as lyophilized live cells reconstituted in facilities). The minimal anticipated treatment benefits will include a > 50% reduction in overall disease burden, a 25% or greater 5-year survival rate (all stages combined), and largely manageable treatment-related morbidities.
Development of Novel Antisense Oligonucleotides to Treat CMT 1A (MU)
Charcot-Marie-Tooth disease (CMT) is defined as a class of hereditary motor and sensory neuropathies of the peripheral nervous system. CMT Is characterized by progressive loss of muscle tissue, touch sensation, and muscle function across various parts of the body, and typically associated with lower limb weakness. It is the most commonly inherited neurological disorder affecting about one in 2,500 people, with over 100,000 patients in the U. S. alone. Clinically, CMT can present early in life, as babies or toddlers are often diagnosed with the disease. Typically, patients experience weakness and muscle atrophy in the lower legs, leading to the classically identifiable high arches, hammertoes, and “clawed feet.” CMT1A, the most common type of CMT, is a duplication of the PMP22 gene that causes an overproduction of PMP22 protein in these patients. Studies show that too much PMP22 inhibits myelination; but when overexpression is relieved, normal myelination initiates within 1 week, suggesting that Schwann cells are present and poised for action. CMT1A is a progressive disease, often leading to a lifelong series of disease management decisions, including the use of braces, surgeries, wheelchair requirements, and ultimately assisted living. Currently, there are no approved therapeutics for any form of CMT and only supportive strategies are available. The proposed innovation is based on the use of modified Antisense Oligonucleotides (ASOs) as drug candidates to alter PMP-22 gene expression by two distinct mechanisms: 1) altering the "splicing" of PMP22, producing a dramatically truncated “out-of-sequence” protein, or, 2) by interfering with the translation of the protein with ASOs that block the translational machinery from producing PMP22 protein. These strategies will have the effect of significantly reducing PMP22 protein expression, thereby mitigating disease development.
Developing Novel Peptide Inhibitors of Beta-Lactam Resistance in MRSA Infections (MU)
Antibiotic resistance is estimated to cause more than 2.8 M infections and 35,000 deaths annually in the U. S. Among them, Methicillin-resistant Staphylococcus aureus (MRSA) infection, categorized as a serious threat by the Centers for Disease Control and Prevention (CDC), is approaching epidemic levels. β-lactam antibiotics (e.g., penicillin and amoxicillin) are a major class of clinical drugs with ideal pharmacokinetic and toxicity properties, but many bacteria have developed resistance to them. The global MRSA drug market, consisting mainly of antibiotics, is expected to surpass $1.3 B by 2026. The major concern with developing new generations of small-molecule antibiotics for MRSA is the rapid development of drug resistance. Current drugs of choice for MRSA infections also present serious side effects and toxicity. To address this unmet need, the team plans to develop a new class of peptide-based drugs with the potential to inhibit β-lactam resistance in MRSA infections. The envisioned novel peptide inhibitor will be co-administered with β-lactam intravenously (IV) for treatment of hospitalized MRSA patients.
Multi-Target Peptide: A Drug to Remember (OUHSC)
Alzheimer’s disease (AD) is a neurodegenerative disease in which brain neurons progressively become damaged and die. As the disease progresses, symptoms of cognitive decline arise and progress to full dementia, followed by a decline in motor functions, and eventually death. AD has been the fastest growing major cause of death in the U. S. since 2000, and became the 6th leading cause of death in 2007. In 2020, 5.8 M Americans were suffering from AD, and the total cost of care for these patients was estimated at $244 B. These numbers are projected to increase by 40% every decade until 2040. Genetic, pathological, and biochemical evidence supports that an early event in AD is the abnormal accumulation of amyloid β (Aβ) peptide in the brain. Passive immunotherapy by injection of anti-Aβ antibodies has been the most successful approach for clearance of Aβ. However, the benefits of these drug candidates remain modest, and the risks of adverse events offset their benefits. In June 2021, a drug candidate with modest efficacy on cognitive decline in early-stage AD patients received a controversial approval by the FDA, the first of its kind for AD disease-modifying drug candidates in 20 years. An important limitation of disease-modifying drugs is thought to be the complex pathogenesis of the disease, making it extremely difficult to control by targeting only one pathway. The two hallmarks of AD are the presence of extracellular amyloid plaques and intracellular neurofibrillary tau tangles. Drugs that target only one of these pathways could fail to efficiently break the vicious cycle in which each pathway amplifies the other. This drug development team is working on a therapeutic that will have the potential to prevent and reverse the aggregation of Aβ into oligomers, preventing and reversing the neurotoxic and pro-inflammatory effects of Aβ. In addition to Aβ, this drug will potentially target specific membrane receptors on neurons and microglia to inhibit neuroinflammation and neurodegeneration. This proposed combination of effects (inhibition/reversion of Aβ oligomer toxicity, and inhibition of receptor activation) is expected to synergistically inhibit the progression of AD.
