Lab In The News
Innovative Synthetic DNA-based Cancer Immunotherapy Approach Shows Tumor-clearing Ability in Preclinical Models
PHILADELPHIA — (April 18, 2019) — Wistar scientists have developed a novel synthetic DNA approach for patient-specific production of cancer-targeting molecules called bispecific T cell engagers.
The Muthumani Laboratory
There are still many deadly infectious diseases that do not have approved vaccines. Over the past 30 years, multiple platforms have been developed to create vaccines that can effectively induce protective immunity. One of the most promising of these platforms is DNA vaccination, which has a remarkable record of safety and immunogenicity in numerous recent clinical trials. DNA vaccines are also very stable at ambient temperatures, making them ideal candidates for distribution in resource-poor communities where vaccine storage infrastructures are unstable and where cancers and serious infectious pathogens remain endemic.
The Muthumani lab performs iterative optimization of vaccine constructs to enhance their immunogenicity. Extensive characterization of the immune responses generated by novel synthetic DNA vaccines in multiple animal models has been carried out. The laboratory also pioneered the field of DNA encoded monoclonal antibodies (DMAbs), which uses synthetic DNA to deliver genes encoding therapeutic monoclonal antibodies (mAbs) against infectious diseases, cancers, or immunomodulation targets, allowing direct in vivo production. The laboratory has made several important contributions in these areas, including novel DNA approaches for Chikungunya virus (CHIKV), Middle East Respiratory Syndrome (MERS), Zika virus (ZIKV), and Mayaro virus (MAYV), among others. Work in the Muthumani lab has contributed to the development of clinical programs for the first ZIKV vaccine (NCT02887482), the first MERS vaccine (NCT03721718), and the first DMAb clinical trial funded by the Bill & Melinda Gates Foundation (BMGF, NCT03831503).
Peng Xiao, Ph.D.
Directing immune responses against emerging infectious diseases
Vaccine approach: We are engineering enhanced synthetic consensus DNA vaccines for use against a range of emerging infectious pathogens infecting humans including CHIKV, MERS virus, ZIKV, Powassan virus (POWV), MAYV, Junin virus (JUNV), Crimean-Congo hemorrhagic fever (CCHFV), West Nile virus (WNV), Dengue virus (DENV) and Nipah virus (NiV). We also engineer various infectious pathogens infecting animals such as African swine fever virus (ASFV), Porcine epidemic diarrhea virus (PEDV) and Foot-and-mouth disease Virus (FMDV). Our second-generation synthetic DNA vaccines incorporate numerous improvements. We measure the in vivo efficacy of these synthetic vaccines in driving protective immunity in a variety of ways, including characterization of the B and T cell immune responses involved in virus neutralization and clearance.
Therapeutic approach: Monoclonal antibody (mAb) therapies have revolutionized the standard of care for a broad spectrum of cancers, but mAb treatments face several challenges regarding delivery and accessibility. Patients currently receive mAb treatment through passive infusion, which can be time-intensive and require repeated treatments. Furthermore, the large-scale production challenges and the need for repeated dosing make mAbs costly, which prevents their broader availability, especially in developing nations. Our lab is therefore exploring the use of second-generation, synthetic plasmid-based antibody production as an alternative to passive mAb administration. We are developing a novel gene delivery system to produce antibodies in vivo.
Immunopathogenesis of viral disease and molecular studies of host-pathogen interactions for drug and immunotherapeutic development
The molecular functions of viral proteins are arguably the most important pathogenic factors during viral infection. Using state-of-the-art virology and immunology tools, we explore the molecular basis of cellular protein functions, the interaction between viral factors and host cell signaling proteins, and general functions of T cells and antigen presenting cells. By studying viral proteins and their interacting cellular partners, our research will provide a deeper understanding of the mechanisms underlying these interactions and guide development of new compounds that block them.
Perales-Puchalt, A., Duperret, E.K., Yang, X., Hernandez, P., Wojtak, K., Zhu, X., Jung, S.H., Tello-Ruiz, E., Wise, M.C., Montaner, L.J., et al. "DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity." JCI Insight. 2019 Apr 18;4(8). pii: 126086. doi: 10.1172/jci.insight.126086. eCollection 2019 Apr 18.
Choi, H., Kudchodkar, S.B., Reuschel, E.L., Asija, K., Borole, P., Ho, M., Wojtak, K., Reed, C., Ramos, S., Bopp, N.E., et al. "Protective immunity by an engineered DNA vaccine for Mayaro virus." PLoS Negl Trop Dis. 2019 Feb 7;13(2):e0007042. doi: 10.1371/journal.pntd.0007042. eCollection 2019 Feb.
Tebas, P., Roberts, C.C., Muthumani, K., Reuschel, E.L., Kudchodkar, S.B., Zaidi, F.I., White, S., Khan, A.S., Racine, T., Choi, H., et al. "Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report." N Engl J Med. 2017 Oct 4. doi: 10.1056/NEJMoa1708120. [Epub ahead of print]
Muthumani, K., Marnin, L., Kudchodkar, S.B., Perales-Puchalt, A., Choi, H., Agarwal, S., Scott, V.L., Reuschel, E.L., Zaidi, F.I., Duperret, E.K., et al. "Novel prostate cancer immunotherapy with a DNA-encoded anti-prostate-specific membrane antigen monoclonal antibody." Cancer Immunol Immunother. 2017 Dec;66(12):1577-1588. doi: 10.1007/s00262-017-2042-7. Epub 2017 Aug 17.
Muthumani, K., Falzarano, D., Reuschel, E.L., Tingey, C., Flingai, S., Villarreal, D.O., Wise, M., Patel, A., Izmirly, A., Aljuaid, A., et al. "A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates." Sci Transl Med. 2015 Aug 19;7(301):301ra132. doi: 10.1126/scitranslmed.aac7462.
Maureen E. Murphy, Ph.D.
Ira Brind Professor and Program Leader, Molecular & Cellular Oncogenesis Program, The Wistar Institute Cancer Center
Associate Vice President for Faculty Affairs
Scientific Director, Histotechnology Facility