Cell: Heavy!

based on engineeringThe therapy of immune cells (that is, genetically engineered immune cells) has recently emerged as a promising approach to treating cancer

based on engineeringThe therapy of immune cells (that is, genetically engineered immune cells) has recently emerged as a promising approach to treating cancer

To overcome these limitations, researchers at the Gladstone Institute and UCSF in a new study systematically analyze the molecular building blocks used to engineer therapeutic cells

"We have identified a number of factors that should greatly facilitate the engineering of therapeutic cells with greater sensitivity, accuracy and safety than previously possible," said Kole Roybal, Ph.

"We have identified a number of factors that should greatly facilitate the engineering of therapeutic cells with greater sensitivity, accuracy and safety than previously possible," said Kole Roybal, Ph.

build better receptors build better receptors

The key to most therapeutic cells is a molecule called a receptor

The key to most therapeutic cells is a molecule called a receptor

This approach was used to create CAR-T cells, which have been shown to be very effective at eliminating certain types of blood cancers

Starting from a different scaffold, Roybal previously developed a receptor called synNotch that can guide T cells to better recognize and kill solid tumors (Cell, 2016, doi:10.

"These smart cell therapies can deliver powerful therapeutic activity precisely at the site of disease, improving efficacy and reducing the chance of life-threatening toxicity in patients," Roybal said

However, the original synNotch receptor has been difficult to deploy in humans for cell-based therapy

To see what they could keep and knock out of the synNotch receptor without losing its desired function, Roybal's team systematically swapped parts of the receptor

"A challenging but intriguing feat is figuring out how different parts of the known receptor work so we can take those parts apart," said co-first author Dr.

Finally, Roybal's team built a catalog of receptors they call SNIPR (synthetic intramembrane proteolysis receptor) that are small enough to be inexpensively engineered in human cells

"Understanding the rules of receptor design allows us to construct receptors that are more efficient and more suitable for clinical translation," said Iowis Zhu, co-first author of the paper and a graduate student in Roybal's lab

A platform for next- generation cell therapy A platform for next-generation cell therapy

The authors next evaluated the role of these optimized receptors inAbility to clear tumors in mouse models of leukemia , mesothelioma, and ovarian cancer

The authors next evaluated the role of these optimized receptors inAbility to clear tumors in mouse models of leukemia , mesothelioma, and ovarian cancer
.
To reduce the chance of killing off-target cells, they combined SNIPR, which is designed to recognize one molecule on the surface of a tumor, with a CAR receptor that has been genetically modified to recognize another tumor molecule
.
Furthermore, they made CAR receptor production dependent on SNIPR receptor activation
.
In this way, only cells that carry the targets of synNotch and the CAR receptor are killed, while cells that carry only one of these targets are not
.
leukemia

Image via Cell, 2022, doi:10.
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Image via Cell, 2022, doi:10.
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In each of the three cancer types they tested, this two-step targeting strategy resulted in more selective elimination of cancer cells than either receptor alone, highlighting the approach's promise to reduce Off-target toxicity of cell therapy
.

In each of the three cancer types they tested, this two-step targeting strategy resulted in more selective elimination of cancer cells than either receptor alone, highlighting the approach's promise to reduce Off-target toxicity of cell therapy
.

SNIPR-based cell therapy is now being optimized for the treatment of ovarian, kidney, prostate and glioblastoma cancers at scientific institutions and a company called Arsenal Bio, co-founded by Roybal
.

SNIPR-based cell therapy is now being optimized for the treatment of ovarian, kidney, prostate and glioblastoma cancers at scientific institutions and a company called Arsenal Bio, co-founded by Roybal
.

Cancer may not be the only disease treatable with SNIPR-based cell therapy
.
This receptor system is also suitable for enhancing the anti-inflammatory activity of immune cells to treat autoimmune diseases
.
Furthermore, SNIPR may potentially be able to be used to targetStem cells or other cell types to detect tissue damage and induce tissue repair or reverse fibrosis
.

Cancer may not be the only disease treatable with SNIPR-based cell therapy
.
This receptor system is also suitable for enhancing the anti-inflammatory activity of immune cells to treat autoimmune diseases
.
Furthermore, SNIPR may potentially be able to be used to targetStem cells or other cell types to detect tissue damage and induce tissue repair or reverse fibrosis
.
stem cell

"Engineered cells have the potential to function as smarter treatments than traditional small molecules and biologics," Roybal said.
"
We hope our new receptor system will serve as a technology platform that enables scientists and clinicians to engineer safer , more targeted and effective cell therapy to fight cancer and many other diseases
.
"

"Engineered cells have the potential to function as smarter treatments than traditional small molecules and biologics," Roybal said.
"
We hope our new receptor system will serve as a technology platform that enables scientists and clinicians to engineer safer , more targeted and effective cell therapy to fight cancer and many other diseases
.
"

References:

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.

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.
Modular design of synthetic receptors for programmed gene regulation in cell therapies

2.
A New Toolkit To Engineer Safe and Efficient Therapeutic Cells
https://gladstone.
org/news/new-toolkit-engineer-safe-and-efficient-therapeutic-cells

2.
A New Toolkit To Engineer Safe and Efficient Therapeutic Cells
https://gladstone.
org/news/new-toolkit-engineer-safe-and-efficient-therapeutic-cells

 

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