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, pastes and particles 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.

Understanding the immunological consequences of cancer ablation

Minimially invasive focal ablation technologies, such as cryoablation (CA), radiofrequency ablation (RFA), microwave ablation (MWA), high intensity focused ultrasound (HIFU), and irreversible electroporation (IRE) are used in the clinical management of multiple, mainly unresectable, solid malignancies. These technologies are capable of generating tumor-specific immunity via in situ vaccination through the release of large amounts tumor antigen together with various immune-stimulating molecules from disrupted cells, e.g., damage-associated molecular patterns (DAMPs), heat shock proteins (HSPs), adenosine triphosphate (ATP), etc.  In turn, robust tumor-specific immune responses should be able to prevent recurrences and eliminate coincident lesions. Unfortunately, clinical evidence of robust antitumor immunity and/or abscopal responses following ablation is rare and unpredictable. For every instance of a spontaneous abscopal tumor regression, there seems to be equal evidence of pro-oncogenic progression. The goal of this research is to define the immune consequences of tumor ablation and to identify the mechanisms by which they hinder the development of antitumor immunity. With multiple collaborators at NC State, UNC and Duke, we are well-positioned to compare the strengths and weaknesses of different clinically relevant ablation modalities. A better understanding of the immunological consequences of ablation will, in the long term, lead to the intelligent design of adjuvant immunotherapies.

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. We are developing a customizable vaccine platform for drugs of abuse like fentanyl. The materials used to create these vaccines offer unprecedented versatility to deliver multiple formats or states of matter to increase both titers and persistence of anti-drug antibodies.

Self-administered vaccines

The COVID19 pandemic revealed significant bottlenecks in healthcare systems worldwide. In developed countries, immunization rates were constrained by the availability of healthcare workers to adminsitered vaccines. In undeveloped countries, immunization rates suffered due to the lack of infrastructure to track, store and distribute vaccines. We are developing thermostable, self-administered vaccines to improve access to life saving immunizations and increase vaccination rates, especially in remote areas or during emergencies.