David Zaharoff, PhD

Research

Mechanisms of localized IL-12 induced tumor regression. We have shown in multiple preclinical tumor models that intratumoral and intravesical administrations of interleukin-12 (IL-12) co-formulated with the polysaccharide, chitosan (CS), can sustain IL-12 in the tumor microenvironment, induce regression of primary tumors and induce tumor-specific immunity that can eliminate distant lesions and cause brisk infiltration of T cells and macrophages. Current research is focused on: 1) evaluating CS/IL-12-induced neoantigen-specific T cell responses; 2) assessing neoantigen-specific memory responses following neoadjuvant CS/IL-12 immunotherapy; and 3) assessing the potential for CS/IL-12-induced in situ vaccination to overcome known primary immunotherapy resistance mechanisms.

Effect of heparin on the immunobiology of IL-12. We have shown IL-12 to be a heparin-binding protein with multiple putative heparin-binding segments on the p40 subunit. Biologically, heparin enhances the activity of IL-12 in diverse cells types although there is likely a species dependent component to then activity enhancement. We also found that heparin recovers the activity of IL-12 in cells with functionally inactive IL-12 receptor subunits. Ongoing research is aimed at determining the effects of heparin length and sulfation on IL-12 activity and defining the interactions of the IL-12/IL-12R/heparin complex. Also, by exploring the potential of heparin to recover IL-12 activity in diverse IL-12Rb1 mutants, we hope to develop a therapeutic strategy for patients with Mendelian susceptibility to mycobacterial diseases (IL-12Rb1 point mutations)

Novel cytokine-polysaccharride bioconjugates. Delivery of cytokines and immunomodulators in hydrogels lessens but does not eliminate their systemic dissemination. In order to completely localize cytokines to an injection site, we are linking them with large, bioadhesive polysaccharides. The positively charged polysaccharides effectively anchor cytokines within a tissue of interest and result in no systemic dissemination, no toxicity while eliminating tumors. This approach can be used to deliver a single cytokine or multiple cytokines simultaneously.

Topical delivery to the esophagus. 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. Despite the incredible burden of esophageal diseases, there are no FDA-approved pharmaceuticals that directly target the esophagus. A poor understanding of the scientific underpinnings of esophageal drug delivery together with a lack of investment in esophagus-targeted drugs has inhibited progress. We are developing mucoadhesive formulations to enhance the deposition and penetration of glucocorticoids in the esophageal wall. We are also exploring the potential for localized/topical delivery of large biologics, such as cytokines or antibodies to inhibit chemotactic signals for problematic inflammatory cells.

Personalized neoantigen-based cancer vaccines. Rapid advances in genomic sequencing have made it feasible to sequence a cancer patient’s tumor(s) and predict unique mutated antigens, or neoantigens. Knowledge of neoantigens can be exploited to create personalized cancer vaccines. Because of the poor immunogenicity of traditional peptide-based vaccines, we are designing a particle-based platform approach that is capable of incorporating multiple neoantigen epitopes as well as immune-stimulating agents such as TLR agonists, STING agonists, and cytokines.

List of Publications