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 Weiner Laboratory
The Weiner laboratory represents one of the pioneering research teams in the field of DNA vaccines and immune therapies. The lab has published more than 400 scientific papers, chapters and reviews, including seminal papers in the DNA vaccine field, and has produced more than 70 patents. Along with collaborators, the Weiner Lab was the first to move DNA vaccines to human clinical studies, establishing their initial safety and immunogenicity. More than a dozen experimental clinical therapies and vaccines have been developed from research from the Weiner laboratory, including the first Zika vaccine in clinical trials, as well as a novel immunotherapy for HPV-associated cancer and precancer.
Weiner’s team was the first to show that a DNA-based approach could impact an HIV model challenge in nonhuman primates. Based on these accomplishments, Weiner contributed to the FDA’s “Points to Consider” guidance document on moving gene based approaches safely to clinical study. Important reports from the Weiner lab include the first DNA vaccine studied for HIV as well as for cancer immune therapy of cutaneous T cell lymphoma, the early development of DNA encoded genetic adjuvants, including IL-12, advances in gene optimization, and advances in electroporation technologies resulting in improved gene delivery.
Makan Khoshnejad, Ph.D.
Research Assistant Professor
Ami Patel, Ph.D.
Elizabeth Parzych, Ph.D.
Emma Reuschel, Ph.D.
Edgar Tello Ruiz
Bill and Melinda Gates Project
The Zika virus has become a global health concern due to its rapid spread and concerning link to microcephaly in infants. The Weiner lab has received funding from the Bill and Melinda Gates foundation for a collaborative project with Inovio Pharmaceuticals and HUMABS BioMed to develop DNA encoded monoclonal antibodies (DMAbs) against Zika. DMAbs are injected into the muscle and the human body is used as its own bioreactor to produce protective antibodies. Working with highly effective antibodies for which sequences were provided by HUMABS, the Weiner lab is optimizing DMAbs for high levels of expression, binding, and neutralization. Once these DMAbs are shown to be protective in mice, they will be tested in nonhuman primates and eventually prepared for clinical trials with the assistance of Inovio.
Ebola virus causes the highly lethal Ebola virus disease (EVD), characterized by a severe hemorrhagic fever and a mortality rate ranging from 50 to 90 percent. The virus was first identified in 1976 and has been responsible for isolated outbreaks. The 2013-2016 EVD outbreak in West Africa was the largest to-date, with more than 28,500 confirmed cases and over 11,000 deaths. This was the first time that cases were confirmed in countries outside of Africa, highlighting concerns that global travel could increase spread of the virus to new populations. There are currently no approved preventative or post-exposure vaccines or therapeutics available for EVD treatment. The Ebola virus is classified as a Category "A" Priority Pathogen by the U.S. Centers for Disease Control and Prevention.
The Weiner lab is a key member of a $45 million collaborative grant from the U.S. Defense Advanced Research Projects Agency (DARPA). This grant is led by Inovio Pharmaceuticals with the goal of utilizing the DNA platform to develop a multi-faceted approach against Ebola virus infection. The Wistar team is involved in the development of DNA-based vaccines against EVD and a DNA-based monoclonal antibody (DMAb) to treat EVD. Other partners on this grant include MedImmune, the Public Health Agency of Canada, and Université Laval.
The team has developed an EVD DNA vaccine that is 100 percent protective in cynomolgus macaques against lethal Ebola virus challenge. This vaccine has entered a Phase I clinical trial (clinicaltrials.gov: NCT02464670).
The team is also working on prevention of related Ebolavirus members Sudan virus (SUDV) and Bundibugyo virus (BDBV), and the related filovirus Marburg virus.
Integrated Preclinical/ Clinical AIDS Vaccine Development Program
The Weiner lab has a long history of working on DNA vaccine for human immunodeficiency virus (HIV). The lab is currently a part of a multi-institutional group working on developing a prophylactic HIV vaccine under a five year Integrated Preclinical/Clinical AIDS Vaccine Development Program grant from the National Institutes of Allergy and Infectious Disease (NIAID). Working with Inovio Pharmaceuticals, Duke University, Emory University, University of Massachusetts and the National Institutes of Health, the group aims to build on the success of previous generations of DNA vaccines in order to induce strong cellular and humoral responses. The main focus of the program is inducing broad responses against the diverse HIV surface protein, Env.
Basser Center for BRCA Project
The Weiner lab has teamed up with investigators at the University of Pennsylvania to develop a novel vaccine to prevent cancer development in high-risk patient populations. This includes individuals who carry mutations in the BRCA1 or BRCA2 genes and are susceptible to the development of breast, pancreatic and ovarian cancer. This novel vaccine encodes the tumor antigen TERT, which is highly expressed in tumor cells, and is particularly high in tumor samples from patients with mutations in DNA damage repair pathways, such as the BRCA1/BRCA2 pathway. The lab developed this vaccine and is currently working to improve the efficacy of the vaccine using combination therapies with immune checkpoint blockade antibodies in mouse models. In parallel, a clinical trial is being conducted for high-risk patients in remission after adjuvant therapy for TERT DNA vaccine with or without IL-12 immune plasmid adjuvant. This project is funded by a Breakthrough Science Team Award through the Basser Research Center for BRCA at the University of Pennsylvania.
Penn/Inovio/MedImmune (PIM) Project
The Weiner lab has formed a collaboration with Inovio Pharmaceuticals and MedImmune to develop DNA-encoded monoclonal antibody (DMAb) against Influenza virus and emerging antibiotic-resistant bacteria, including Pseudomonas aeruginosa and Staphylococcus aureus. This program is funded by the Defense Advanced Research Projects Agency (DARPA). Highly-engineered monoclonal antibody sequences are encoded in a DNA plasmid and delivered directly into cells of the body using electroporation, resulting in protective monoclonal antibodies "manufactured" in the body – versus recombinant proteins manufactured and purified in vitro. Given the scalability of DNA manufacturing and ease of DNA delivery relative to conventional recombinant protein monoclonal antibody therapies, the DMAb platform has potential to greatly expand the market for monoclonal antibody prophylaxis/therapy against challenging infectious disease targets.
Duperret, E.K., Trautz, A., Weiner D.B., et al. "Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice." Clin Cancer Res. 2018 Mar 1;24(5):1190-1201. doi: 10.1158/1078-0432.CCR-17-2033. Epub 2017 Dec 21.
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., Boyer, J., Park, Y.K., Trottier, S., Remigio, C., Krieger, D., Spruill, S.E., Bagarazzi, M., Kobinger, G.P., Weiner, D.B., Maslow, J.N. "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]
Patel, A., DiGiandomenico, A., Weiner, D.B., et al. "An engineered bispecific DNA-encoded IgG antibody protects against Pseudomonas aeruginosa in a pneumonia challenge model." Nat Commun. 2017 Sep 21;8(1):637. doi: 10.1038/s41467-017-00576-7.
Elliott, S.T.C., Kallewaard, N.L., Weiner, D.B., et al. "DMAb inoculation of synthetic cross reactive antibodies protects against lethal influenza A and B infections." NPJ Vaccines. 2017 Jul 6;2:18. doi: 10.1038/s41541-017-0020-x. eCollection 2017.
Trimble, C.L., Morrow, M.P., Kraynyak, K.A., Shen, X., Dallas, M., Yan, J., Edwards, L., Parker, R.L., Denny, L., Giffear, M., Brown, A.S., Marcozzi-Pierce, K., Shah, D., Slager, A.M., Sylvester, A.J., Khan, A., Broderick, K.E., Juba, R.J., Herring, T.A., Boyer, J., Lee, J., Sardesai, N.Y., Weiner, D.B., Bagarazzi, M.L. "Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial." Lancet. 2015 Nov 21;386(10008):2078-2088. doi: 10.1016/S0140-6736(15)00239-1. Epub 2015 Sep 17.
Ashani Weeraratna, Ph.D.
Ira Brind Professor
Professor & Co-Leader, Immunology, Microenvironment & Metastasis Program
Member, The Wistar Institute Melanoma Research Center