Author: The Wistar Institute

PHILADELPHIA — (Sept. 27, 2018) — Scientists at The Wistar Institute have implemented a novel structurally designed synthetic DNA vaccine to simultaneously target multiple members of a family of proteins that are specifically overexpressed in several types of cancer. This approach addressed a difficult issue in cancer immunotherapy, specifically how to simultaneously drive antitumor immune responses against multiple tumor antigens in a single, easily delivered formulation. The new strategy could simplify immunotherapy treatment and may prevent cancer escape from immune pressure as the immune system could attack the cancer at multiple susceptible target points. The new vaccine, targeting the human cancer-associated MAGE-A family of proteins, is effective and safe in a melanoma preclinical model, as described in a paper published online in Clinical Cancer Research.

Because their expression is restricted to tumor cells, proteins belonging to the MAGE-A family represent promising targets for immunotherapy. Yet, cancer vaccines targeting the original MAGE-A3 member, which has the highest expression in several solid tumors, have thus far failed to demonstrate efficacy in clinical trials.

In an attempt to solve this conundrum and advance the clinical applications of this promising immunotherapy, researchers at Wistar performed a thorough analysis of the expression levels of all the twelve proteins in the MAGE-A family in human cancers. They observed that many of the MAGE-A members, and not just MAGE-A3, are highly expressed on tumor cells in several cancer types, some of them being present simultaneously in the same patient. These findings suggest that previous vaccines
with limited focus on one target were likely not effective in driving strong T-cell immunity because of the natural immune dampening system known as immune tolerance.

“The combination of structural design and synthetic DNA technology offers ample flexibility and specificity in the development of a designer target immunogen,” said lead researcher David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. “We amalgamated structurally relevant primary sequences from multiple MAGE-A members, obtaining an optimized consensus DNA vaccine capable of targeting seven MAGE-A family members simultaneously. This vaccine is recognized by the host immune system much more robustly, resulting in improved immune performance.”

Tested in mice, the vaccine induced immune cross-reaction with multiple MAGE-A proteins and induced a robust CD8+ T cell-mediated immune response.

“CD8+ T cells are the predominant effectors in the response to immunotherapy; we can think of them as the Navy Seals of cancer immunology,” added Weiner.

Importantly, the vaccine significantly slowed tumor growth and prolonged survival in a mouse model of melanoma. The researchers observed reduced invasion in the skin, which was associated with accumulation of CD8+ T cells into the tumors, demonstrating the ability of the vaccine to drive antitumor immunity of importance for melanoma therapy.

“Our cross-reactive vaccine has a significant advantage in preventing tumor escape compared to previously designed MAGE-A3-specific vaccines,” said Elizabeth K. Duperret, Ph.D., postdoctoral fellow in the Weiner Lab and first author on the study. “Patients whose tumors express multiple members of this family of antigens represent an important group to study the benefits of this immunotherapy approach.”

This work was supported by National Institutes of Health grants SPORE P50CA174523 and F32 CA213795. Additional funding was provided by the W.W. Smith Charitable Trust, the Basser Foundation and a grant from Inovio Pharmaceuticals, Inc. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30 CA010815.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer and infectious disease research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

PHILADELPHIA — (Sept. 6, 2018) — Currently available vaccines for the prevention of seasonal influenza virus infection have limited ability to induce immunity against diverse H3N2 viruses, an influenza A subtype that has led to high morbidity and mortality in recent years.

Now, Wistar scientists have engineered a synthetic DNA vaccine shown to produce broad immune responses against these H3N2 viruses. Study results were published online in the journal Human Gene Therapy.

The recent severe influenza seasons in 2013/2014, 2014/2015 and 2017/2018 can be directly attributed to H3N2. Commercial vaccine efficacy against H3N2 in 2017/2018 was low and contributed to a greater rate of pneumonia and influenza-associated deaths.

“Current vaccine design and manufacturing to meet the antigenic diversity of H3N2 viruses is challenging, and with another flu season approaching there remains a pressing need for new vaccine approaches for influenza,” said lead researcher David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center at The Wistar Institute, and W.W. Smith Charitable Trust Professor in Cancer Research. “There is also a need for improvements in rapid selection and deployment against newly emergent viral strains and synthetic DNA vaccines represent an important tool to reach this goal.”

To overcome the antigenic diversity of H3N2 viruses, Weiner and colleagues used H3N2 strains from 1968 to the present retrieved from the Influenza Research Database to generate four synthetic common sequences of the hemagglutinin antigen (HA), a protein present on the viral surface. These micro-consensus sequences were used to generate four DNA vaccines that were co-mixed to create a cocktail vaccine labeled pH3HA. The scientists administered the vaccine or placebo to mice and a booster vaccine two weeks later. Two weeks after the booster injection, they inoculated them with two representative influenza viruses.

Sarah Elliot, Ph.D., a senior postdoctoral fellow in the Weiner Lab, and colleagues monitored clinical signs, body weight and survival for two weeks after infection. All mice immunized with the synthetic DNA vaccine developed broad, robust antibody responses against HA and effective cellular immune responses including CD4 and CD8 T cell responses.

They were protected against lethal influenza A infection from two different challenge H3N2 viruses. Vaccination with pH3HA induced robust antibodies against the 1968 pandemic H3N2 as well as contemporary H3N2 strains that were components of commercially available vaccines from 2015/2016 and 2017/2018.

Compared with those who received placebo, immunized mice survived intranasal virus challenge with 10 times the median lethal dose; the placebo group succumbed to infection within six days of exposure to the challenge virus.

“The pH3HA vaccine represents a unique micro-consensus approach to producing immune responses to antigenically related — yet diverse, seasonal influenza A H3N2 viruses,” Weiner said. “The overarching goals of this approach are to limit the number of vaccine reformulations that can be deployed to protect against novel H3N2 viruses.”

This work was supported by a grant from the National Institutes of Health. Co-authors of this study from The Wistar Institute include Sarah Elliott, Amelia Keaton, Jacqueline Chu and Ami Patel. Other co-authors include Charles Reed, Bradley Garman, Jian Yan, and Kate Broderick from Inovio Pharmaceuticals, Inc.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

PHILADELPHIA — (Sept. 5, 2018) — A combination of a novel inhibitor of the protein CK2 (Casein kinase 2) and an immune checkpoint inhibitor has dramatically greater antitumor activity than either inhibitor alone, according to research from The Wistar Institute that was published online in Cancer Research.

Immune checkpoint inhibitors have been approved to treat several types of cancer, including some types of lung cancer and colon cancer, but not all patients who receive these immunotherapeutics gain benefit from them. A better understanding of the molecular reasons why some patients do not respond to immune checkpoint inhibitors could identify new therapeutic targets for combination treatments that may improve clinical outcomes.

“A population of immune cells called myeloid-derived suppressor cells (MDSC) has been implicated in tumor resistance to various types of cancer treatment, including immune checkpoint inhibitors,” said lead researcher Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment & Metastasis Program at Wistar. “We have previously shown that accumulation of the most abundant type of MDSC, polymorphonuclear MDSC (PMN-MDSC), is caused by downregulation of Notch signaling, in part as a result of CK2 activity.”

Based on these previous results, Gabrilovich and collaborators set out to investigate whether combining inhibitors of CK2 with immune checkpoint inhibitors could improve immune responses in mouse models of cancer and to determine what mechanisms of action caused the results they obtained.

“Our new data suggest that using a CK2 inhibitor to manipulate the tumor microenvironment may sensitize patients to the effect of an immune checkpoint inhibitor and thereby improve clinical outcomes, although this needs to be tested in clinical trials,” said Ayumi Hashimoto, a postdoctoral fellow in the Gabrilovich Lab and first author on the paper.

The researchers found that a combination of the CK2 inhibitor BMS-595 and the immune checkpoint inhibitor anti-CTLA-4-mIgG2a had antitumor activity in three different mouse models of cancer: a lung cancer, a colon cancer, and a lymphoma model. More than 60 percent of mice who received the combination treatment completely eliminated the tumor while none of the mice that received either single agent alone completely eliminated the tumor.

The mechanism of the effect of BMS-595 was analyzed, and in-depth studies showed that two of the main types of immune cells affected by the CK2 inhibitor in tumor-bearing mice were PMN-MDSCs and another type of myeloid cell called tumor-associated macrophages (TAMs). The frequency of PMN-MDSCs was not significantly altered in tumors, but it was substantially decreased in the spleen, an organ that is a part of the immune system. TAMs were decreased in the tumor.

“Our study shows that CK2 inhibition blocks the differentiation of PMN-MDSCs and TAMs, meaning that it blocked the generation of these cells from their precursors. This led to a decrease in immunosuppressive PMN-MDSCs and tumor-promoting TAMs and thus to a substantial augmentation of the antitumor activity of immune checkpoint blockade,” added Gabrilovich.

The research was supported by National Institutes of Health grant RO1 CA084488 and a grant from Bristol-Myers Squibb. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Wistar co-authors include Ayumi Hashimoto, Jerome Mastio, and Andrew Kossenkov. Other co-authors include Scott I. Abrams from Roswell Park Comprehensive Cancer Center; and Chan Gao, Ashok V. Purandare, Heshani Desilva, Susan Wee, John Hunt, and Maria Jure-Kunkel from Bristol-Myers Squibb.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

PHILADELPHIA — (August 2, 2018) — The Wistar Institute announces that the Pennsylvania Department of Labor & Industry Secretary Jerry Oleksiak will address graduates from The Wistar Institute’s Biomedical Research Technician (BRT) Apprenticeship and Biomedical Technician Training (BTT) Program, both of which incorporate science, technology, engineering, mathematics (STEM), and non-traditional training to support the development of the biotech labor force in Pennsylvania.

“This 2018 graduating year of biomedical research technicians represents a first for Wistar as we are proud to graduate two inaugural students who have completed our first-of-its-kind, nontraditional, credentialed BRT Apprenticeship program alongside our 12 BTT Program graduates,” said Dr. William Wunner, Wistar director of outreach education and technology training, and director of academic affairs. “Our apprenticeship and pre-apprenticeship programs feed into the region’s strength in the life sciences by developing experienced research technicians who can add to the vital workforce.”

Governor Wolf’s PAsmart initiative is a new way of thinking about job training and workforce development, by providing targeted funding for apprenticeship programs, STEM education, computer science, and more, so students and workers get the training and skills needed for in-demand, middle class jobs. The first-of-its-kind $30 million investment will help students and workers gain real-world skills for the 21st century economy.

“Employers across Pennsylvania need skilled workers with the hands-on training that programs and apprenticeships like this provide,” said Secretary Jerry Oleksiak. “Today’s graduates were trained in industry-grade laboratories and have the skills to get good jobs in the science and research sector throughout our commonwealth.”

Secretary Oleksiak addressed educators, parents, local business leaders, and students graduating from the BTT Program and the BRT Apprenticeship program. The BTT Program was created in 2000 as a partnership between The Wistar Institute and the Community College of Philadelphia to reinforce the region’s workforce with experienced lab technicians. In 2017, L&I’s Apprenticeship and Training Office approved and registered the institute’s BRT Apprenticeship program, which expands upon the BTT Program’s structure.

“We are excited to witness the first two BRT Apprentices graduate in the first in kind career path apprenticeship and enter a sustainable and vibrant workforce in biomedical research,” said Dr. Donald Generals, president of the Community College of Philadelphia. “This model will expand to support the development of the region’s growing and industrious biomedical and biotech labor force.”

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Community College of Philadelphia is the largest public institution of higher education in Philadelphia and the sixth largest in Pennsylvania. The College enrolls approximately 34,000 students annually and offers day, evening, and weekend classes, as well as classes online.

For more information about pursuing an education and career in Pennsylvania at any stage of life, visit PAsmart.