Development of Localized Immunotherapies
Immunotherapy has revolutionized the way in which cancer is treated. However, there is much room for improvement. Currently approved immunotherapies do not benefit the majority of patients and carry significant side effects associated with their systemic administration. We believe that a safer and more effective approach is to deliver and maintain immunotherapies directly to the tumor microenvironment. To this end, we are developing, injectable hydrogels that are capable of sustaining high levels of co-formulated immunomodulatory agents in an injected tumor. We are also creating novel immunocytokines in which potent cytokines are fused to tumor-binding elements.
Development of intravesical immunotherapies for bladder cancer
Abscopal responses following intravesical immunotherapy. C57BL/6 mice were implanted with MB49 either subcutaneously (a, c) or both subcutaneously and orthotopically (b, d). Mice in groups C (n = 5) and D (n = 10) received intravesical treatments of chitosan/IL-12 (CS/IL-12) (1 μg) twice per week starting 7 days after implantation. Group B (n = 4) received intravesical PBS. Group A (n = 5) served as a negative control. Tumor volume, hematuria, and overall survival were monitored. Arrows indicate treatments.
Bladder cancer is the fifth most common non-cutaneous cancer diagnosis in the U.S. with an estimated 79,030 new cases and 16,870 deaths in 2017. Although 70-80% of patients are diagnosed with early stage non-muscle invasive bladder cancer (NMIBC), bladder cancer has a recurrence rate of approximately 65%. Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been standard-of-care intravesical therapy for high risk NMIBC for more than 30 years. Yet, 20-30% of patients will fail initial BCG therapy and 30 - 50% of BCG responders will develop recurrent tumors within 5 years. The inability of BCG to induce tumor-specific immunity necessitates long-term maintenance therapy and continuous surveillance of bladder cancer patients. As a result, domestic bladder care expenditures are significant, >$4 billion per year, and bladder cancer has the highest lifetime treatment costs per patient of all cancers.
The overall goal of this research is to develop an intravesical immunotherapy capable of eliciting tumor-specific immune responses in order to limit the progressive recurrence of high-grade NMIBC. IL-12 is under investigation as a candidate to replace BCG. Our previous studies demonstrated that chitosan, a mucoadhesive, natural polysaccharide derived from the exoskeletons of crustaceans, can enhance the delivery and antitumor efficacy of intravesically administered IL-12.3,7 In fact, a co-formulation of chitosan solution and recombinant IL-12 (chitosan/IL-12) was found to eliminate established orthotopic bladder tumors in 80-100% of mice. Furthermore, recent data demonstrated that mice develop systemic tumor-specific protective immunity following intravesical chitosan/IL-12 immunotherapy. Specifically, all cured mice rejected a distant, subcutaneous challenge with the original MB49 bladder tumor but not an irrelevant B16 melanoma. Furthermore, intravesical chitosan/IL-12 immunotherapy was found to induce abscopal responses, i.e. regression of uninjected tumors, when an orthotopic bladder tumor was present. To our knowledge, these data are the first to show that an intravesical immunotherapy can induce systemic and abscopal tumor-specific immune responses.
Understanding the immunological consequences of cryoablation
Modern cryosurgery, or cryoablation (CA), of solid tumors has been routinely practiced since the reproducible production of supercooled gases in 1960s. CA is generally inferior to surgical resection, yet it has an important and growing role in the minimally invasive management of smaller tumors and for cancer patients who are ineligible for surgery. With the emergence of cancer immunotherapy in the past decade, there has been renewed interest in improving the oncological outcomes of tumor ablation through combination with approved and experimental immunotherapies. Indeed, several ablation-immunotherapy combinations have demonstrated improved efficacy in pre-clinical studies. However, clinical results have not been as promising. Although enticing, the goal of this project is NOT to screen different combinations of immunotherapies and CA preclinically in an attempt to pick a ‘winner’ for clinical translation. Instead, the proposed research will be the first to comprehensively characterize the tumor-immune dynamics following CA. In particular, we hope to understand why CA-induced immune responses are not able to prevent recurrences despite the elimination of nearly all tumor cells and with the release of substantial tumor antigen and immunostimulatory molecules. A better understanding of the immunological consequences of CA will, in the long term, lead to the intelligent design of adjuvant therapies for CA and other tumor ablative technologies.
Vaccination against unintentional overdose
Lethal drug overdoses have skyrocketed in the past five years due to adulteration of illicit drugs with fentanyl and fentanyl analogs. Roughly one-half to two-thirds of illicit opioids are now laced with fentanyl unbeknownst to the consumer. Given the low lethal dose of fentanyl, estimated at 2mg, unintentional fentanyl overdose is becoming increasingly common. Naloxone is an opioid receptor antagonist that can reverse fentanyl overdose. However, the limited accessibility of naloxone precludes its widespread use. Additional strategies capable of preventing lethal fentanyl overdoses are desperately needed.
Several anti-fentanyl vaccines in preclinical development have shown impressive induction of anti-fentanyl antibodies capable of reducing fentanyl uptake in the brain and inhibiting its anti-nociceptive activity. These vaccines are patterned after previous anti-drug vaccines which, for nearly 50 years, have involved the conjugation of drug haptens to immunogenic carrier proteins. Despite the extensive history of anti-drug vaccine development, clinical success has been elusive. Highly variable and transient antibody responses among human populations are major obstacles. Current anti-fentanyl vaccines will face similar concerns regarding potency and durability during clinical translation.
To address antibody titer and persistence concerns, this project will develop a novel vaccine platform based upon conjugating haptens to the polysaccharide chitosan (CS) rather than an immunogenic protein. CS is a natural polysaccharide that has been extensively explored in drug and vaccine delivery applications. The versatility of CS makes it a particularly attractive carrier molecule on multiple levels. First, CS can be produced with a wide range of polymer lengths and its amine groups allow for facile conjugation of haptens at a range of densities. These two features offer unprecedented customization. Furthermore, CS can be formulated as an injectable solution or as antigen-encapsulating nano- or microparticles. Both forms have been shown to enhance immune responses against co-delivered vaccine antigens. Lastly, CS has bioadhesive properties which can be exploited in a mucosal vaccine platform. Heterologous vaccinations using mixed routes of immunization and diverse vaccines may increase antibody titers and persistence.
Development of topical esophageal delivery systems
Esophageal diseases, including gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), eosinophilic esophagitis (EoE), and esophageal cancer, are collectively a rapidly increasing cause of morbidity. GERD causes symptoms of heartburn, regurgitation, and chest pain, and is one of the most common medical conditions, seen in up to a third of all individuals. It is increasing in incidence and prevalence and is a major driver of healthcare utilization. GERD can be complicated by erosive esophagitis, esophageal strictures, and Barrett’s esophagus (BE). BE is a risk factor for esophageal adenocarcinoma (EAC) and is seen in approximately 2-3% of the U.S. population. EoE is a chronic allergic disease of the esophagus that causes trouble swallowing due to esophageal strictures. It has rapidly emerged as an important esophageal condition, with greater than 5-10 fold increases in incidence and prevalence over the past decade. The estimated prevalence for EoE is at least 1 in 2000 Americans while EoE-associated healthcare costs are about $1.4 billion per year. EoE is now the most common cause of food impaction, responsible for >50% of impaction-related emergency room visits, and the second most common cause of esophagitis. Up to 23% of all patients undergoing endoscopy for dysphagia will have EoE. Lastly, the incidence of EAC, in contrast to the decreasing incidence rates of many malignancies, has increased faster than any other cancer. Treatments for esophageal cancer remain ineffective, and the overall 5-year survival is dismal at 18%. Despite the incredible burden of esophageal diseases, there are no FDA-approved pharmaceuticals that directly target the esophagus. The overall goal of this research is to develop an orally administered topical delivery system to target esophageal disorders.