Three projects awarded LDER funding to explore innovations

Each year, the Frederick National Laboratory offers its scientists an opportunity to compete for funding to conduct the research they view as critical to advance biomedical research but is outside the scope of their daily research activities.  

This year, three proposals earned funding through the program, known as the Laboratory Directed Exploratory Research (LDER) program. The LDER program, which was modeled after the U.S. Department of Energy’s Laboratory Directed Research and Development program, is designed to foster innovation and collaboration across the laboratory. It has funded 37 projects since its launch in 2015.  

The three innovative new projects are described below: 

Contextualizing tumor heterogeneity with spatial transcriptomics 

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Elijah Edmondson, D.V.M., Ph.D., a staff pathologist in the Laboratory Animal Sciences Program, said he has had his eye on the LDER program since he joined the FNL in 2016, and this year he decided it was time to apply.  

“I want to make a tangible difference in cancer research,” he said. “And the LDER is an opportunity to do that by providing the means to explore innovative ideas.” 

For his LDER project, Edmondson assembled a team with expertise in pathology, animal models, cancer genetics and spatial technologies to gain a more holistic view of the tumor landscape.  

Tumor heterogeneity—the diversity of individual cells within a tumor—poses a substantial challenge to developing effective cancer therapies. However, knowing the spatial context of each cell within a tumor can help researchers understand how cancer cells spread and change, and consequently develop better therapies. New spatial transcriptomic technologies, which can measure and map gene expression activity across a tissue sample, can provide that insight.  

Edmondson explained that “this spatial approach will allow us to characterize these models with a granularity never before possible, enabling a better understanding of (1) which preclinical models are appropriate for which human diseases and (2) how drug therapies perturb transcription and in which cell types. These two things are crucial to the goal of identifying new cancer therapies.” 

Expanding Autographa californica multiple nucleopolyhedrovirus transgene insertion sites 

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Baculoviruses, a type of virus that attacks arthropods, are important tools for creating proteins for use in biomedical research and gene therapies. Scientists insert new genes into the virus’ DNA to make the infected insect cells synthesize specific proteins of interest, known as recombinant proteins. 

Carissa Grose and Matt Drew of the Protein Expression Laboratory are co-leading a project to increase protein yields and stability by changing the site where the scientists insert the target genes into the baculoviruses’ DNA. They have already identified several promising new sites.   

“Commercially available baculovirus expression systems utilize only the polyhedrin locus for insertions of transgenes,” Grose said. “This is a region of known instability, and as we demonstrated previously, higher protein expression and stability can be achieved at alternative locations. This LDER funding will give the insect cell expression community new options for recombinant protein expression and recommendations for insertion methods based on the goals for their final products.” 

Grose explained that, if successful, the impact of this project could be substantial.

“These efforts will assist in the reduction of process costs, and ultimately dosage costs, for gene therapies, pesticides or other baculovirus-produced treatments for the larger community,” she said. 

Simian immunodeficiency virus specific T-cell receptor engineered cells with costimulatory signaling domains

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T-cells, a type of white blood cell that helps fight off infection, can limit AIDS viral replication to an extent. However, the natural T-cell response cannot readily control or clear the virus.  

Adrienne Swanstrom, Ph.D., a scientist within the AIDS and Cancer Virus Program, is leading a LDER project that seeks to improve upon the natural T-cell response, making it better able to fight off the virus. To do this, her team will engineer T-cells to express a virus-specific T-cell receptor modified with additional costimulatory signaling domains. Co-stimulatory domains provide a secondary signal to trigger the immune response. Different costimulatory domains can provide advantageous characteristics to the T-cell.  

“I hope my project will improve the design of T-cell receptor constructs used in immunotherapy and give us the ability to enhance properties of engineered cells such as persistence and effector function, which are a key correlate of in vivo efficacy,” Swanstrom explained. “This project attempts to fill a gap in the general immunotherapy field, which has not comprehensively evaluated the impact of adding costimulatory domains in tandem with a T-cell receptor.” 

She noted that improvements in engineered T-cells would also have impacts beyond HIV research and “more broadly may enable improved engineered T cell designs for the cancer immunotherapy field.”