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“Next-Gen Smart CAR-T Therapy: Targeted Tumor Killing with Modular SNIPR Receptors”
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Next-Gen Smart CAR-T Therapy: Targeted Tumor Killing with Modular SNIPR Receptors.
Cell: Breakthrough! Next-generation, Smarter cell therapy unveiled! CAR-T cells with modular SNIPR receptors efficiently kill solid tumors while reducing toxic side effects.
Researchers from the Gladstone Institutes and the University of California, San Francisco, have conducted a systematic analysis of molecular components used to design therapeutic cells in a groundbreaking study.
Therapies based on engineered immune cells, specifically gene-modified immune cells, have recently emerged as a promising approach for cancer treatment. Engineered immune cells demonstrate superior precision and accuracy in detecting and eliminating cancer cells compared to traditional drugs.
However, cell-based therapies still face significant limitations, including toxicity and the potential to attack healthy cells.
Additionally, scientists have not fully mastered how to genetically modify existing therapeutic cells to expand their applications or better control their activity.
To overcome these limitations, researchers from the Gladstone Institutes and the University of California, San Francisco, systematically analyzed molecular components used to design therapeutic cells in a new study.
Their research provides comprehensive guidelines for designing therapeutic cells with increased specificity, safety, and ultimately customizing cell-based therapies. The results of this research were published in the April 14, 2022, issue of the journal Cell, titled “Modular design of synthetic receptors for programmed gene regulation in cell therapies.”
Dr. Kole Roybal, an associate professor in the Department of Microbiology and Immunology at the University of California, San Francisco, and the corresponding author of the paper, stated, “We have identified principles that should greatly enhance the engineering of therapeutic cells to make them more sensitive, precise, and safe. Our research provides a toolkit for biomedical scientists to guide a range of cell-based therapies to their intended targets and program their therapeutic activities.”
Building Better Receptors
The key to most therapeutic cells is a molecule called a receptor. Receptors are large proteins that span the cell’s outer membrane. Their extracellular portions can recognize specific targets, such as proteins on the surface of cancer cells, while their intracellular portions instruct the cell on what to do upon recognizing the target. One approach to designing therapeutic cells is to insert synthetic receptors composed of segments from known receptors into the cell, typically immune cells called T cells.
This method has been used to construct CAR-T cells, which have been highly effective in eliminating certain types of blood cancers. CAR-T cells carry a “chimeric antigen receptor (CAR),” which is derived from receptors commonly found in T cells.
Starting from different frameworks, Dr. Roybal previously developed a receptor called synNotch, which could guide T cells to better recognize and kill solid tumors (Cell, 2016, doi:10.1016/j.cell.2016.09.011). Since that early research, Dr. Roybal’s lab has demonstrated how synNotch can be used in combination with CARs to develop next-generation cell therapies for ovarian cancer and mesothelioma (Science Translational Medicine, 2021, doi:10.1126/scitranslmed.abd8836). SynNotch receptors allow scientists precise control over when and where therapeutic T cells are active.
Roybal explained, “These intelligent cell therapies can precisely deliver potent therapeutic activity at disease sites, enhancing efficacy and reducing the risk of life-threatening toxicities for patients.”
However, the original synNotch receptor was challenging to deploy for cell-based therapies in humans. It was bulky, making it difficult to insert into human cells, and some of its parts came from mice, yeast, and viruses rather than human receptors, which could lead to immune rejection when engineered cells were introduced into patients.
To understand what they could retain and eliminate from the synNotch receptor without losing its desired functionality, Roybal’s team systematically swapped out different parts of the receptor. After inserting the modified synNotch receptors into human T cells, they tested their ability to recognize target molecules and activate the expected responses.
Dr. Raymond Liu, a co-first author of the paper and a postdoctoral fellow in the Roybal lab, explained, “A challenging but fascinating endeavor was figuring out how different parts of known receptors function so that we could dissect these parts and reassemble them in novel ways to meet our design requirements.”
Finally, the Roybal team cataloged a receptor they called SNIPR (synthetic intramembrane proteolysis receptor) that was small enough for cost-effective engineering in human cells. SNIPR receptors were entirely composed of human receptor segments and could detect and respond to small amounts of targets. Furthermore, SNIPR’s activity could be tuned so that cells carrying it not only killed target cells but also delivered specific molecules to precise disease locations.
Iowis Zhu, a co-first author of the paper and a graduate student in the Roybal lab, noted, “Understanding the rules of receptor design enables us to construct more effective receptors that are also better suited for clinical translation.”
The Next Generation of Cell Therapy Platform
The authors then assessed the ability of these optimized receptors to clear tumors in mouse models of leukemia, mesothelioma, and ovarian cancer. To reduce the chances of killing non-target cells, they combined SNIPR, designed to recognize one molecule on the tumor surface, with a CAR receptor engineered to recognize another tumor molecule. Additionally, they made the production of the CAR receptor dependent on the activation of the SNIPR receptor. This way, only cells carrying both synNotch and CAR receptors would be killed, while cells carrying only one of the target molecules would not be affected.
In each of the three cancer types they tested, this two-step targeting strategy resulted in more selective elimination of cancer cells than using either receptor alone, highlighting the potential of this approach to reduce off-target toxicity in cell therapy.
Based on SNIPR, cell therapies are now being optimized for the treatment of ovarian cancer, kidney cancer, prostate cancer, and glioblastoma in research institutions and a company co-founded by Dr. Roybal called Arsenal Bio.
Cancer may not be the only disease treatable with SNIPR-based cell therapy. This receptor system may also be applicable for enhancing the anti-inflammatory activity of immune cells to treat autoimmune diseases. Additionally, SNIPR may have the potential to target stem cells or other cell types to detect tissue damage and induce tissue repair or fibrosis reversal.
Dr. Roybal concluded, “Engineered cells have the potential to act as smarter therapies than traditional small molecules and biologics. We hope that our new receptor system will serve as a technology platform enabling scientists and clinicians to design safer, more targeted, and more effective cell therapies for combatting cancer and many other diseases.”
1. Zhu, I., Liu, R., & Roybal, K. (2022). Modular design of synthetic receptors for programmed gene regulation in cell therapies. Cell, 2022, doi:10.1016/j.cell.2022.03.023.
2. A New Toolkit To Engineer Safe and Efficient Therapeutic Cells. Gladstone Institutes. (2022). https://gladstone.org/news/new-toolkit-engineer-safe-and-efficient-therapeutic-cells
Next-Gen Smart CAR-T Therapy: Targeted Tumor Killing with Modular SNIPR Receptors
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