Our work in collaboration with Dr. Peng Qiu’s group on a computational method to select libraries of promiscuous substrates that can classify mixtures of proteases was published in Cell Reports Methods! Congratulations to Brandon and the team! Read the full manuscript here.
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
Our work on antigen-presenting nanoparticles that allow rapid ligand exchange for mRNA delivery to multiple antigen-specific T cells in vivo was published in Science Advances! Congratulations to Ida and the team! Read the full manuscript here.
Our work on mathematical modeling to predict prodrug escape and treatment success of protease-activated antibacterial prodrugs was published in Molecular Systems Biology! Congratulations to Brandon and the team! Read the full manuscript here.
Glympse Bio’s work on multiplexed protease sensors for urinary monitoring of nonalcoholic steatohepatitis was published in Science Translational Medicine! Congratulations to Gabe and the team! Read the full manuscript here.
Summary | Nonalcoholic steatohepatitis (NASH) is a type of fatty liver disease that has been dubbed the silent epidemic as it has few symptoms. When left undiagnosed and untreated, the liver can develop cirrhosis or liver cancer. We developed synthetic biomarkers to diagnosis NASH early, monitor changes in disease severity, and indicate response to treatment.
Our review entitled “Synthetic biomarkers: a twenty-first century path to early cancer detection” was published in Nature Reviews Cancer! Congratulations to Gabe and the team! Read the full manuscript here.
Summary | In 2019, the NCI Division of Cancer Prevention co-organized a think tank meeting on synthetic biomarkers for early detection. We wrote this review to summarize the current science and as a clarion call for more scientists and engineers to work together to solve this important problem. We also dedicated the article to the late Dr. Sam Gambhir, a visionary pioneer and thought leader in bioengineering who devoted his career to developing methods for early disease detection.
A team of researchers led by bioengineers at the Georgia Institute of Technology is expanding the precision and ability of a revolutionary immunotherapy that is already transforming oncology. CAR T-Cell therapy has been hailed by patients, clinical-researchers, investors, and the media as a viable cure for some cancers.
CAR T-Cell therapy involves engineering a patient’s T-cells, a type of white blood cell, in a lab. Then a chimeric antigen receptor (CAR) is added, and these customized immune cells are returned to the patient’s body, where they seek and destroy cancer cells. That’s how it works, when it works.
It’s a new, evolving, and booming area of immunotherapy, with more than 500 clinical trials analyzing CAR T-cells for cancer treatment going on right now around the world.
“These therapies have proven to be remarkably effective for patients with liquid tumors – so, tumors that are circulating in the blood, such as leukemia,” said Gabe Kwong, associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. “Unfortunately, for solid tumors – sarcomas, carcinomas – they don’t work well. There are many different reasons why. One huge problem is that the CAR T-cells are immunosuppressed by the tumor microenvironment.”
Kwong and his collaborators are changing the environment and making some cell modifications of their own to enhance the way CAR T-cells fight cancer. They’ve added a genetic on-off switch to the cells and a developed a remote-control system that sends the modified T-cells on a precision invasion of the tumor microenvironment, where they kill the tumor and prevent a relapse. And they explain it all in a study published recently in the journal Nature Biomedical Engineering.
The latest study builds on the lab’s body of work exploring remotely controlled cell therapies, in which the researchers can precisely target tumors, wherever they are in the body, with a local deposition of heat. “And this heat basically activates the CAR T-cells inside the tumors, overcoming the problems of immunosuppression,” said Kwong.
In the earlier study, the researchers did not clinically treat tumors, but they are doing that now with the new work. To generate heat in a mouse’s tumor, they shone laser pulses from outside the animal’s body, onto the spot where a tumor is located. Gold nanorods delivered to the tumor turn the light waves into localized, mild heat, raising the temperature to 40-42 Celsius (104-107.6 F), just enough to activate the T-Cells’ on-switch, but not so hot that it would damage healthy tissue, or the T-cells. Once turned on, the cells go to work, increasing the expression of cancer-fighting proteins.
The real novelty, Kwong said, was in genetically engineering clinical-grade CAR T-Cells, something the team worked on for the past three years. Now, in addition to a switch that responds to heat, the researchers have added a few upgrades to the T-cells, rewiring them to produce molecules to stimulate the immune system.
Localized production of these potent, engineered proteins (cytokines and Bispecific T-cell Engagers) has to be controlled precisely.
“These cancer-fighting proteins are really good at stimulating CAR T-cells, but they are too toxic to be used outside of tumors,” said Kwong. “They are too toxic to be delivered systemically. But with our approach we can localize these proteins safely. We get all the benefits without the drawbacks.”
The latest study shows the system cured cancer in mice, and the team’s approach not only shrunk tumors but prevented relapse – critical for long-term survival. Further studies will delve into additional tailoring of T-cells, as well as how heat will be deposited at the tumor site. A gentle laser was used to heat the tumor site. That won’t be the case when the technology moves on to human studies.
“We’ll use focused ultrasound, which is completely non-invasive and can target any site in the body,” Kwong said. “One of the limitations with laser is that it doesn’t penetrate very far in the body. So, if you have a deep-seated malignant tumor, that would be a problem. We want to eliminate problems.”
The research was funded by the NIH Director’s New Innovator Award (DP2HD091793), the National Center for Advancing Translational Sciences (UL1TR000454), and the Shurl and Kay Curci Foundation.
CITATION: Ian C. Miller, Ali Zamat, Lee-Kai Sun, Hathaichanok Phuengkham, Adrian M. Harris, Lena Gamboa1, Jason Yang7, John P. Murad7, Saul J. Priceman, Gabriel A. Kwong. “Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control.” (Nature Biomedical Engineering, August 2021)
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Our work on engineering CAR T cells to turn on and fight cancer in response to localized heat was published in Nature Biomedical Engineering! Congratulations to Ian, Ali, and the team! Read the full manuscript here.
Summary | Treating solid tumors with chimeric antigen receptor (CAR) T cells typically results in poor responses. In this study, we developed a new class of CAR T cells that are switched on by localized heating to release potent biologics that are otherwise too toxic to use systemically. Thermal targeting of CAR T cells opens the door for spatial control to potentiate cancer therapy.
Press Coverage | Georgia Tech Research Horizons “Heat-controllable CAR T-cells destroy tumors and prevent relapse in new study” | TheScientist “Heating up CAR T cells for cancer therapy” | GEN “CAR T gets hot under the collar for cancer targets” | Mirage News | Newswise | MedicalXpress | The Medical News | Technology Networks | AZO Life Sciences | Front Line Genomics | Science Daily
Our review on biomaterials that interface with synthetic immunity to improve engineered T cell therapies is published in Advanced Healthcare Materials! Congrats to Ida, Quoc, and the team! Read the manuscript here.
Our work on synthetic antigen-presenting cells for antigen-specific activation of T cells was published in Advanced Therapeutics! Congratulations to Shreyas, Anna, and the team! Read the full manuscript here.