Congratulations to Sofia and Elif for winning President’s Undergraduate Research Salary Awards (PURA) for Spring 2023! PURA funds student salaries to conduct undergraduate research with Georgia Tech faculty and offsets travel expenses for undergraduates to present their research at professional conferences. Read more about PURA here.
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Leonard “Lenny” Rogers joins LSI as a new post-doc. Lenny is from Kansas City, Missouri, and completed his Ph.D. at Washington University in St. Louis, where he developed an intracellular arginine sensor to track resistance to arginine deprivation therapy and discovered an important new mechanism of resistance to this therapy working with Prof. Brian Van Tine. Read more about Lenny here.
Dr. Gabe Kwong is the first faculty member at Georgia Tech to be awarded the prestigious NIH Director’s Pioneer Award! This award is the NIH’s largest grant in the High-Risk, High-Reward Research program and will provide LSI $5.5 million over the next five years to, in the words of Dr. Kwong, “develop a living sensor – immune cells that can traffic through the body and act as a long-lived pool of sentinels.” Read more below about LSI’s exciting new project, titled “Finding Sleeping Beauty: T Cell Biosensors for Dormant Cancer Detection”:
Summary | Some types of cancers, such as estrogen receptor positive breast cancer, can recur as metastatic disease many years or even decades following a dormancy period where the patient displays no clinical symptoms. Currently, there is no widely used method to monitor the dormant state nor its reawakening. The arrival of cancer immunotherapy has revealed exciting possibilities using engineered T cells as living medicines to achieve striking responses in patients with cancers that were previously untreatable. This moment is an opportunity to not only build a future where T cells are engineered as therapies, but also as living sensors that can detect cancer with sensitivities and specificities beyond what is currently possible. This project seeks to engineer T cells as ultrasensitive biosensors to detect dormant cancer and when they reawaken by amplifying the release of synthetic biomarkers (blood, urine and imaging) for detection. These technological breakthroughs will have huge implications in understanding how and when dormant cells reawaken and guide therapeutic interventions at the earliest stages of reactivation.
Press Coverage | Georgia Tech College of Engineering “A Record Four Researchers Win NIH Director’s Awards” | Georgia Tech Biomedical Engineering “Kwong using NIH Director’s Pioneer Award to Develop Living Biosensors”
LSI is excited to welcome new graduate students Chloé Thiveaud, Eric Lee, Jamey Siebart, and Sean Chan! Chloé completed her bachelors at Georgia Tech while working as an undergraduate researcher in LSI. Eric graduated from UC Berkeley and worked on CAR T cell therapy at City of Hope before joining LSI. Jamey received a B.S. in Bioengineering at the University of Washington while researching optogenetic biosensors. Sean worked on non-viral transfection at Rubius Therapeutics after completing B.S. and M.S. degrees at UMichigan and Johns Hopkins, respectively. Read more about our new lab members here.
The National Institute of Biomedical Imaging and Bioengineering at the National Institute of Health is funding a collaborative project led by LSI and Dr. Stanislav Emelianov’s Ultrasound Imaging and Therapeutics Research Laboratory. In this project, we will engineer gold nanorod labeled CAR T cells to track delivery of CAR T cells to tumors, remotely activate CAR T cells to enhance their local potency, and monitor key CAR T cell functions within the tumor microenvironment.
Summary | The limited ability to control adoptively transferred CAR T cells at sites of disease contributes to poor anti-tumor responses against solid malignancies. This proposal seeks to develop an image-guided therapy based on photothermal activation of CAR T cells to increase treatment precision and improve patient responses.
Aparna was born in Chennai, India, and grew up in Atlanta, GA. She graduated with a B.S. in Biomedical Engineering from Georgia Tech and is currently enrolled in the Masters of Biomedical Innovation and Development program at Georgia Tech. As an undergrad, Aparna was involved with several Global Health projects, where she designed solutions for fetal heart rate monitoring, detecting early onset of preeclampsia and preventing neonatal hypothermia. In her free time, Aparna loves to cook, travel, read, and spend time with her friends and family.
Ali was awarded the Ruth L. Kirschstein Predoctoral Individual National Research Service Award – i.e., the F31 fellowship – by the National Cancer Institute of the National Institutes of Health to sponsor his project entitled “Focused ultrasound control of intratumoral NKG2DL BTE production by CAR T cells to potentiate epitope spread.” Congrats to Ali!
Summary | To enhance CAR T cells for solid tumors, potent immunomodulators such as cytokines or bispecific T cell engagers (BTEs) can be co-infused. However, systemic delivery of these agents breaches self-tolerance resulting in numerous immune related adverse effects. This proposal seeks to use focused ultrasound to non- invasively control the intratumoral production of BTEs by thermal sensitive CAR T cells to enhance anti-tumor activity and elucidate mechanisms of epitope spread by investigating DC priming of endogenous T cells.
The National Institute of Allergy and Infectious Diseases at the National Institutes of Health is sponsoring LSI’s work on DNA-gated sorting (DGS) cytometry for multiplexed isolation of Ag-specific CD8 T cells.
Summary | Ag-specific CD8 T cells express T cell receptors (TCRs) that recognize antigens in the form of processed peptides bound to major histocompatibility complex class I (MHCI) molecules. In healthy individuals, the CD8 TCR repertoire comprises approximately 106–108 different cell populations. Soluble pMHCI multimers are widely used to enumerate and isolate Ag-specific T cells by fluorescence activated cell sorting (FACS); however, FACS has limitations including low-throughput, high shear-stress damage (especially to rare cells), and low multiplexing depth due to limited number of fluorophores. For high-throughput cell sorting (>106 cells) such as for manufacturing T cell therapies, magnetic activated cell sorting (MACS) is commonly used but can only produce antibody-enriched or depleted cell fractions, and cells sorted by positive selection remain labeled with beads, preventing immediate downstream assays such as phenotyping by flow analysis. New approaches are needed for multiplexed, high-throughput and label-free isolation of Ag-specific T cells. This proposal will develop DNA- gated sorting (DGS) cytometry for multiplexed isolation of Ag-specific CD8 T cells. DGS comprise a molecular DNA circuit that couples a magnetic bead to pMHCI molecules through DNA hybridization, and that functions as a sorting ‘gate’ to capture, release, and recover Ag-specific T cells by toehold-mediated strand displacement. By using orthogonal DNA strand displacement reactions, a library of beads coated with different pMHCI antigens can simultaneously capture target cell populations en masse and each subpopulation can then be eluted by sequential strand displacement. In contrast to fluorophores, the number of possible DNA sequences to design strand displacement reactions scales exponentially by the length n of the DNA oligo (i.e., 4n), providing the possibility to extend this technology to isolate Ag-specific T cells at depths that is currently not possible. This proposal will also implement DGS with pMHCI monomers that multimerize when hybridized onto the bead to produce the required binding avidity for T cell capture, but after cell release, revert into monomers to dissociate from T cells resulting in label-free isolates. It will also implement light-induced peptide exchange to produce large pMHCI libraries to integrate with multiplexed DGS. Finally, this proposal will demonstrate an important application for the manufacturing of chimeric antigen receptor (CAR) T cells using virus-specific T cells to redirect them to tumor cells, using key benchmarks such as ex vivo functional assays (expansion, transduction efficiency, cytotoxicity) and in vivo therapy in mice bearing CD19+ cancer cells.
Cindy grew up in Hefei, China. She graduated with a B.S. in Biological Sciences from the University of California, Davis, and a M.S. in Environmental Sciences from Emory University. As a graduate researcher in Dr. Eri Saikawa’s lab, she studied heavy metal soil contamination and developed phytostabilization methods for lead remediation. Upon graduating, she worked for RayBiotech where she focused on research and development of antibodies and antibody-based research tools, especially COVID-19 related. Cindy spends her free time playing with her cats, watching anime, playing video games, and exploring hiking trails near Atlanta.
Urinary biomarkers of immunotherapy response and resistance published in Nature Biomedical Engineering
Our work on multiplexed protease activity sensors conjugated to checkpoint antibodies to discriminate early responses and resistance to immune checkpoint blockade was published in Nature Biomedical Engineering! Congratulations to Quoc, Anirudh, and the team! Read the full manuscript here.
Summary | Since 2014, the FDA has approved 7 immune checkpoint inhibitors, but not all patients benefit from therapy. We developed a new class of immune checkpoint inhibitor that is attached with protease sensors for early detection of drug treatment. In preclinical studies, we found that these therapeutic sensors can indicate early responses before future changes in tumor volume, and can identify different types of resistance as they emerge.
Press Coverage | Georgia Tech Research “Kwong lab develops biosensors for quick assessment of cancer treatment” | Inside Precision Oncology “Biosensors created to detect early response to immune checkpoint blockade” | MedicalXpress | Technology.org | EurekAlert! | ScienMag | Newswise | Bioengineer.org | The Medical News | Technology Networks | ecancer