Breakthrough! Next-Generation Smarter Cell Therapy Unveiled!

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Breakthrough! Next-Generation Smarter Cell Therapy Unveiled!

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Cell: Breakthrough! Next-Generation, Smarter Cell Therapy Unveiled! CAR-T Cells Expressing Modularized SNIPR Receptors Efficiently Kill.

Researchers from the Gladstone Institutes and the University of California, San Francisco, have conducted a systematic analysis of molecular components used in designing therapeutic cells in a groundbreaking study.

Therapies based on engineered immune cells, known as genetically modified immune cells, have recently emerged as a promising approach for cancer treatment. Engineered immune cells demonstrate greater precision and accuracy in detecting and eliminating cancer cells compared to traditional drugs. However, cell-based therapies still face significant limitations, including potential toxicity and the possibility of inadvertently attacking healthy cells. Additionally, scientists have struggled to effectively 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 in designing therapeutic cells in a new study. Their research has provided comprehensive guidelines for designing therapeutic cells with higher specificity and safety, ultimately paving the way for customized cell-based treatment approaches. The results of their study were published in the April 14, 2022 issue of Cell journal, 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 advance 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 activity.”

Building Better Receptors

The key to most therapeutic cells is a molecule called a receptor, which is a large protein spanning the cell’s outer membrane. The extracellular portion of receptors can recognize specific targets, such as proteins on the surface of cancer cells, while their intracellular portion instructs 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 cells, typically immune cells known as T cells.

This approach has been used to create CAR-T cells, which have proven 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 a different framework, 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, 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 enable scientists to precisely control when and where therapeutic T cells are active.

Roybal explained, “These intelligent cell therapies can release potent therapeutic activity precisely at disease sites, enhancing efficacy and reducing the risk of life-threatening toxicity to patients.”

However, the original synNotch receptor was challenging to deploy for cell-based therapy in humans. Firstly, it was relatively large, making it difficult to insert into human cells. Additionally, some parts of synNotch were derived from mice, yeast, and viruses rather than human receptors, potentially leading to immune rejection when engineered cells entered a patient’s body.

To understand what they could retain and remove from the synNotch receptor without compromising its desired functionality, Roybal’s team systematically swapped various parts of the receptor. After inserting the modified synNotch receptors into human T cells, they tested their ability to recognize predetermined targets and activate the expected responses.

Dr. Raymond Liu, a postdoctoral scholar in Roybal’s lab and co-first author of the paper, said, “A challenging yet fascinating endeavor was figuring out how different parts of known receptors function so that we could dissect these parts and then reassemble them in new ways to meet our design requirements.”

Ultimately, Roybal’s team constructed a catalog of receptors called SNIPR (synthetic intramembrane proteolysis receptor) that were small enough for cost-effective engineering in human cells. They were entirely composed of human receptor segments and could detect and respond to small quantities of targets. Moreover, SNIPR’s activity could be adjusted so that the cells carrying them not only killed target cells but also delivered specific molecules to precise disease locations.

Iowis Zhu, a graduate student in Roybal’s lab and co-first author of the paper, said, “Understanding the rules of receptor design enables us to construct more effective receptors that are also better suited for clinical translation.”

The Next-Generation Platform for Cell Therapy

The authors then assessed the ability of these optimized receptors to clear tumors in mouse models of leukemia, mesothelioma, and ovarian cancer.

o reduce the chance of killing non-target cells, they combined SNIPR, which was engineered to recognize one molecule on the tumor surface, with CAR receptors engineered to recognize another tumor molecule.

Furthermore, they made the production of CAR receptors dependent on the activation of SNIPR receptors. This way, only cells carrying both synNotch and CAR receptors would be killed, while cells carrying only one of the target molecules would not.

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, renal cancer, prostate cancer, and glioblastoma in research institutions and a company co-founded by Roybal called Arsenal Bio.

Cancer may not be the only disease treatable with SNIPR-based cell therapy. This receptor system is also applicable to enhancing the anti-inflammatory activity of immune cells for treating autoimmune diseases. Additionally, SNIPR may be used to target stem cells or other cell types for detecting tissue damage and inducing tissue repair or fibrosis reversal.

Roybal concluded, “Engineered cells have the potential to serve as smarter therapeutic approaches 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 combating cancer and many other diseases.”

Breakthrough! Next-Generation Smarter Cell Therapy Unveiled!

References:

1. Iowis Zhu et al. 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
https://gladstone.org/news/new-toolkit-engineer-safe-and-efficient-therapeutic-cells

(source:internet, reference only)

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