Vision: Engineer immune system to treat cancer and infectious diseases

Immunoengineering has revolutionized myriad diseases, including cancer, auto-immune diseases, and infectious diseases. The complexity of the structure and function of the human immune system requires expertise in principles of multiscale engineering, data analytics and artificial intelligence, and fundamental immunology and biological sciences. CEPM focuses on two broad aspects of immunengineering: cancer immunotherapy and infectious disease.

Cancer immunotherapy has emerged as an effective regimen alone or in combination with other treatments, such as surgery, chemotherapy, and radiation therapy. With the rapid increase in our understanding of the immune system, an increasing number of small molecules, peptides, recombinant antibodies, vaccines, and cellular therapeutics have been applied to manipulate the immune response for cancer treatment. These immunotherapies have provided significant benefits in the fight against cancer, especially the application of immune checkpoint inhibitors and cell-based therapies. CEPM is addressing cancer immunotherapy alone and in combination with antibodies and small molecule chemotherapeutics to overcome immune-driven immunosuppression, address safer and more effective therapeutics, and develop personalized treatment strategies.

Viral disease has come to the forefront as a result of COVID-19 and the potential for new and emerging infectious agents leading to epidemics and global pandemics. Furthermore, the rise of antibiotic resistance is driving the search for entirely new approaches to tackle microbial infection and contamination. To address these societal problems, CEPM is working on multiple interdisciplinary fronts including new immunomodulation, high-throughput screening and drug repurposing for antiviral agents, microbial drug resistance, and biomanufacturing.

Project Name: Joint project on UV to disinfect exhaled air from non-invasive ventilators (CPAPs)

PIs: Richard Vincent (Mount Sinai), James Paredes (inventor), David Rapoport, MD (Mount Sinai), Adolfo Garcia-Sastre , PhD (Mount Sinai), Robert Karlicek, PhD (RPI), Priti Balchandani, PhD (Mount Sinai)

Abstract: In collaboration with RPI, a device is being developed that that uses UV lamps to disinfect exhaled air from a continuous positive airway pressure (CPAP) machine that has been pulled into a tube/chamber. This prevents air with COVID-19 virus from entering the room and helps solve the problem of aerosolized virus infecting caregivers.
An initial prototype of a devices was developed that that uses UV lamps to disinfect exhaled air from a continuous positive airway pressure (CPAP) machine. This was integrated into a novel experimental setup to generate aerosolized virus and recover it in a biosampler safely, was developed and tested. H1N1 was mist nebulized and recovered in a BSL2 facility. Verified live virus was able to complete the circuit from nebulization to biosampler. We achieved and measured high levels of UV emissions within the prototype device.
Once efficacy against H1N1 is established, we will test the device for efficacy against SARS-CoV-2 in a BSL3 facility.

Project Name: Elucidating the structural determinants of heparan sulfate as a viral co-receptor.

PIs: Jonathan Dordick, PhD (RPI), Mattheos Koffas, PhD (RPI)

Abstract: Glycosaminoglycans (GAGs) play a significant role in viral infection. In particular, heparan sulfate (HS) acts as a co-receptor of myriad viruses, including SARS-CoV-2, the causative agent of COVID-19, several other coronaviruses, respiratory syncytial virus (RSV), varicella zoster, vaccinia, and others. In the case of SARS-CoV-2, the binding of viral spike glycoprotein (SGP) to epithelial HS positions the virus to the ACE-2 receptor, ultimately leading to infection. Thus, HS structure (i.e., variable degrees of N- and O-sulfation, and variable positions of O-sulfation) plays a key role in infectivity and understanding the precise structural features of HS that influence viral infectivity. It is also a key factor in providing new routes to therapeutics and prophylactics.

As part of the immuno-engineering activity of CEPM, we are gaining a mechanistic understanding of the role of HS structure on viral infectivity using SARS-CoV-2 as a primary, and timely, model. Heparin, a highly sulfated GAG, has been shown to be very effective in blocking SARS-CoV-2 from infecting human cells. Similarly, other sulfated polysaccharides and GAGs, including a non-anticoagulant heparin precursor, seaweed fucoidans, and pentosan polysulfate, can block cellular infection of SARS-CoV-2. We are using CRISPR-based genetic switches to modulate HS biosynthetic pathways, alter HS structure, with a particular focus on the degree and location of sulfation, and lead to structure-activity (infectivity) relationships and improved mechanistic understanding. Our guiding hypothesis is that specific HS structural features influence viral infectivity and that understanding the mechanism behind the effectiveness of these structural moieties will lead to new therapeutic and/or prophylactic strategies to combat SARS-CoV-2 VOC. We also hope to understand key mechanisms of virus-host cell interactions among a wide range of viruses. Finally, mechanistic insight gleaned from our work, when coupled to the expanding knowledge of HS structure and distribution in various tissues and under various disease states, may provide information on what makes an individual susceptible toward current and future SARS-CoV-2 VOC and related pathogens.

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