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December 31, 2021/MedClub News/--At present, a variety of immunotherapies and small molecule drugs have been approved for the treatment of liver cancer, but some patients with liver cancer lack response to the treatment drugs, and there are some potentials Side effects and other issues
.
Therefore, the current treatment methods are still inadequate, and more new therapies that are constantly improving are needed
.
Recently, a team of scientists from the Swiss Federal Institute of Technology Zurich has developed a logic-gated AAV gene therapy, which is used in combination with Roche's antiviral drug Cytovene (ganciclovir) in a mouse model of hepatocellular carcinoma It shows the potential of precisely targeting cancer cells, and can kill cancer cells more effectively while preserving healthy tissues, significantly reducing the tumor burden of hepatocellular carcinoma mice
.
The relevant research results were published on Science Translational Medicine on December 15
.
Targeted therapy refers to a treatment method that targets an already clear carcinogenic site at the cellular and molecular level
.
The site can be a protein molecule inside the tumor cell, or it can be a gene fragment
.
Although targeted therapies can be used for cancer, these targets are rarely unique to cancer cells
.
The genetic "logic gate" developed by the research team can distinguish tumor cells from non-tumor cells based on molecular profiles
.
They believe that "logic gates" can process different molecular signal inputs and take corresponding actions, and improve targeting accuracy, which may improve the accuracy of cancer treatment
.
Using "gated" systems to improve safety and effectiveness Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide
.
According to statistics, more than 750,000 people worldwide suffer from hepatocellular carcinoma each year, most of which occur in Asia, and almost half of the cases are in China
.
Liver cancer cells express not only the transcription factors HNF1A and HNF1B, but also overexpress tumor-related transcription factors SOX9 and SOX10
.
The research team designed an "AND" gate, which will only work when both HNF1A/B and SOX9/10 are present in the cells to achieve the purpose of treatment
.
However, some healthy liver cells also express SOX9.
In order to improve targeting accuracy, the researchers added a "NOT" gate, which can close the system when miRNAs that are highly expressed in healthy cells rather than tumor cells are identified
.
After several rounds of screening and testing, the researchers finally identified let-7c, one of the let-7 gene family
.
Let-7 is one of the most widely studied miRNAs, with a length of 21 nt, which is highly conservative, sequential, and tissue cell specific
.
The miRNA shows a significant difference in activity between healthy liver cells and liver cancer cells, and also shows strong activity in other organs
.
Studies have found that let-7 not only directly or indirectly regulates genes related to cell cycle and cell division, regulates tumor cell proliferation, but also inhibits tumor angiogenesis and cancer invasion and metastasis
.
The "logic gate" system developed by the team is compatible with AAV carriers
.
Based on the different molecular profiles of tumor and non-tumor cells, the researchers designed an AAV-encoded gene therapy model that performs molecular scale calculations on multiple miRNA transcription and input to guide herpes virus thymidine kinase (HSV-TK) Activation of effector genes
.
The researchers then paired the "logic gate" with the HSV-TK gene
.
If the cell successfully passes the "logic gate", it will trigger the HSV-TK protein production mechanism, which can convert Cytovene into an effective compound that kills cancer cells
.
The results of this study showed that in the mouse model of liver cancer, the "logic gate" AAV gene therapy and Cytovene combination therapy significantly reduced the tumor burden in mice without significant side effects
.
The control group treated with placebo or Cytovene alone showed exponential tumor growth
.
In addition, mice treated with the combination therapy of "AND" gate and Cytovene only showed strong anti-tumor effects at first, but over time, the overall health of the mice continued to deteriorate, and they lost weight after receiving the treatment.
Side effects
.
Yaakov (Kobi) Benenson, author of the study and co-founder of Pattern BioSciences, said, “The company aims to develop programmable cancer gene therapies using gene circuit technology
.
The
company’s goal is to promote new types of cancer with higher specificity and safety.
Liver cancer therapy
.
In addition, the company is also seeking more cooperation opportunities to expand the technology to other indications, such as the central nervous system and inflammatory diseases
.
"Programmable cell and gene therapies are expected to overcome the challenges of existing therapies with traditional drugs (such as , Small molecule and antibody drugs) usually work by targeting disease-causing proteins and blocking their functions
.
However, these drugs are static, and their effects cannot be adjusted after being administered to the patient
.
In contrast, living-cell drugs are dynamic and will continue to change in the human body, and the treatment principles and effects in the body are also more complicated
.
However, although living cell drugs are expected to achieve change, their application scope is still narrow, and there are limitations such as side effects, immune escape, and limited durability
.
If synthetic biology is used to create next-generation cell and gene therapies, these shortcomings can be overcome and help treat or even cure many complex diseases
.
▲Image source: Senti Bio gene circuit can be considered as a kind of "software" that can be installed in almost any cell or gene therapy mode ("hardware")
.
Gene circuits that perform complex functions are a system composed of three different modules: a sense module that detects disease biomarkers; a compute module that converts inputs to outputs: for example, its design can use Boolean logic to convert specific combinations of inputs into Purpose output; analog operation circuit can also be used, similar to a "varistor"; respond output module that performs one or more therapeutic functions
.
Gene circuit is a multi-component biological structure that can sense input and produce output
.
In this figure, the input is shown on the left, the gene circuit is shown in the middle, and the output is shown on the right
.
(Image source: Senti Bio) "Logic gate" empowers the next generation of "smart" cells and gene therapy logic gated gene circuit technology has shown great potential in the field of cancer treatment.
It can simultaneously find multiple targets to solve tumor cells And it is expected to avoid high toxicity
.
Based on logic gated gene circuit technology, California biotechnology company Senti Bio has developed several innovative CAR-NK cell therapies
.
These CAR-NK cells can distinguish between tumor-related antigens and antigens produced by healthy cells, and ultimately achieve the goal of protecting healthy cells and killing cancer cells accurately and effectively
.
In November this year, Senti Bio presented the preclinical data of the logically gated allogeneic CAR-NK cell therapy SENTI-401 for the treatment of colorectal cancer at the 36th Annual Meeting of the Society for Cancer Immunotherapy (SITC)
.
SENTI-401 aims to use gene circuits to create a gating system with computer logic in human cells to target and kill tumor cells expressing carcinoembryonic antigen (CEA), while preventing the killing of healthy epithelial cells expressing CEA
.
SENTI-401 pairs CEA targeting activated CAR (aCAR) with inhibitory CAR (iCAR), which is responsible for identifying safe antigens (SA) uniquely expressed in certain healthy gastrointestinal tract and lung epithelial cells
.
Preclinical data shows that CAR-NK cells of the logic gate control system can prevent healthy tissue cells from becoming toxic
.
▲The transformation of CAR-NK based on the logic gate control system (picture source: Senti Bio) Recommended reading: "Logic gate" CAR-NK, empowering the next generation of "smart" cells and gene therapyYi Mai Meng broke the news in December, Senti Bio also announced the preclinical results of another logic-gated allogeneic CAR-NK cell therapy SENTI-202 at the annual meeting of the American Society of Hematology (ASH)
.
SENTI-202 is used for the potential treatment of acute myeloid leukemia (AML), which can more precisely target and eliminate cancer cells while preserving healthy tissue
.
"Existing cancer therapies usually only target a single tumor-associated antigen, which means that they can only be used safely and effectively if the antigen is expressed on tumor cells
.
"Senti Bio R&D Deputy Director Dr.
Alba Gonzalez said, "The exciting thing about our'logic gate' technology platform is that it has the potential to advance a very novel CAR-NK-based treatment method that can be more precise Treating a variety of solid tumors, while reducing the risk of targeted, non-tumor toxicity, which may increase the treatment window and provide patients with meaningful benefits
.
"▲Gene circuit applied to cell and gene therapy (picture source: Senti Bio) Recommended reading: Create a "smarter" CAR-NK, Lu Guanda's star company announced its listingYi Mai Meng broke the news reference materials: 1.
https://
.
Therefore, the current treatment methods are still inadequate, and more new therapies that are constantly improving are needed
.
Recently, a team of scientists from the Swiss Federal Institute of Technology Zurich has developed a logic-gated AAV gene therapy, which is used in combination with Roche's antiviral drug Cytovene (ganciclovir) in a mouse model of hepatocellular carcinoma It shows the potential of precisely targeting cancer cells, and can kill cancer cells more effectively while preserving healthy tissues, significantly reducing the tumor burden of hepatocellular carcinoma mice
.
The relevant research results were published on Science Translational Medicine on December 15
.
Targeted therapy refers to a treatment method that targets an already clear carcinogenic site at the cellular and molecular level
.
The site can be a protein molecule inside the tumor cell, or it can be a gene fragment
.
Although targeted therapies can be used for cancer, these targets are rarely unique to cancer cells
.
The genetic "logic gate" developed by the research team can distinguish tumor cells from non-tumor cells based on molecular profiles
.
They believe that "logic gates" can process different molecular signal inputs and take corresponding actions, and improve targeting accuracy, which may improve the accuracy of cancer treatment
.
Using "gated" systems to improve safety and effectiveness Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide
.
According to statistics, more than 750,000 people worldwide suffer from hepatocellular carcinoma each year, most of which occur in Asia, and almost half of the cases are in China
.
Liver cancer cells express not only the transcription factors HNF1A and HNF1B, but also overexpress tumor-related transcription factors SOX9 and SOX10
.
The research team designed an "AND" gate, which will only work when both HNF1A/B and SOX9/10 are present in the cells to achieve the purpose of treatment
.
However, some healthy liver cells also express SOX9.
In order to improve targeting accuracy, the researchers added a "NOT" gate, which can close the system when miRNAs that are highly expressed in healthy cells rather than tumor cells are identified
.
After several rounds of screening and testing, the researchers finally identified let-7c, one of the let-7 gene family
.
Let-7 is one of the most widely studied miRNAs, with a length of 21 nt, which is highly conservative, sequential, and tissue cell specific
.
The miRNA shows a significant difference in activity between healthy liver cells and liver cancer cells, and also shows strong activity in other organs
.
Studies have found that let-7 not only directly or indirectly regulates genes related to cell cycle and cell division, regulates tumor cell proliferation, but also inhibits tumor angiogenesis and cancer invasion and metastasis
.
The "logic gate" system developed by the team is compatible with AAV carriers
.
Based on the different molecular profiles of tumor and non-tumor cells, the researchers designed an AAV-encoded gene therapy model that performs molecular scale calculations on multiple miRNA transcription and input to guide herpes virus thymidine kinase (HSV-TK) Activation of effector genes
.
The researchers then paired the "logic gate" with the HSV-TK gene
.
If the cell successfully passes the "logic gate", it will trigger the HSV-TK protein production mechanism, which can convert Cytovene into an effective compound that kills cancer cells
.
The results of this study showed that in the mouse model of liver cancer, the "logic gate" AAV gene therapy and Cytovene combination therapy significantly reduced the tumor burden in mice without significant side effects
.
The control group treated with placebo or Cytovene alone showed exponential tumor growth
.
In addition, mice treated with the combination therapy of "AND" gate and Cytovene only showed strong anti-tumor effects at first, but over time, the overall health of the mice continued to deteriorate, and they lost weight after receiving the treatment.
Side effects
.
Yaakov (Kobi) Benenson, author of the study and co-founder of Pattern BioSciences, said, “The company aims to develop programmable cancer gene therapies using gene circuit technology
.
The
company’s goal is to promote new types of cancer with higher specificity and safety.
Liver cancer therapy
.
In addition, the company is also seeking more cooperation opportunities to expand the technology to other indications, such as the central nervous system and inflammatory diseases
.
"Programmable cell and gene therapies are expected to overcome the challenges of existing therapies with traditional drugs (such as , Small molecule and antibody drugs) usually work by targeting disease-causing proteins and blocking their functions
.
However, these drugs are static, and their effects cannot be adjusted after being administered to the patient
.
In contrast, living-cell drugs are dynamic and will continue to change in the human body, and the treatment principles and effects in the body are also more complicated
.
However, although living cell drugs are expected to achieve change, their application scope is still narrow, and there are limitations such as side effects, immune escape, and limited durability
.
If synthetic biology is used to create next-generation cell and gene therapies, these shortcomings can be overcome and help treat or even cure many complex diseases
.
▲Image source: Senti Bio gene circuit can be considered as a kind of "software" that can be installed in almost any cell or gene therapy mode ("hardware")
.
Gene circuits that perform complex functions are a system composed of three different modules: a sense module that detects disease biomarkers; a compute module that converts inputs to outputs: for example, its design can use Boolean logic to convert specific combinations of inputs into Purpose output; analog operation circuit can also be used, similar to a "varistor"; respond output module that performs one or more therapeutic functions
.
Gene circuit is a multi-component biological structure that can sense input and produce output
.
In this figure, the input is shown on the left, the gene circuit is shown in the middle, and the output is shown on the right
.
(Image source: Senti Bio) "Logic gate" empowers the next generation of "smart" cells and gene therapy logic gated gene circuit technology has shown great potential in the field of cancer treatment.
It can simultaneously find multiple targets to solve tumor cells And it is expected to avoid high toxicity
.
Based on logic gated gene circuit technology, California biotechnology company Senti Bio has developed several innovative CAR-NK cell therapies
.
These CAR-NK cells can distinguish between tumor-related antigens and antigens produced by healthy cells, and ultimately achieve the goal of protecting healthy cells and killing cancer cells accurately and effectively
.
In November this year, Senti Bio presented the preclinical data of the logically gated allogeneic CAR-NK cell therapy SENTI-401 for the treatment of colorectal cancer at the 36th Annual Meeting of the Society for Cancer Immunotherapy (SITC)
.
SENTI-401 aims to use gene circuits to create a gating system with computer logic in human cells to target and kill tumor cells expressing carcinoembryonic antigen (CEA), while preventing the killing of healthy epithelial cells expressing CEA
.
SENTI-401 pairs CEA targeting activated CAR (aCAR) with inhibitory CAR (iCAR), which is responsible for identifying safe antigens (SA) uniquely expressed in certain healthy gastrointestinal tract and lung epithelial cells
.
Preclinical data shows that CAR-NK cells of the logic gate control system can prevent healthy tissue cells from becoming toxic
.
▲The transformation of CAR-NK based on the logic gate control system (picture source: Senti Bio) Recommended reading: "Logic gate" CAR-NK, empowering the next generation of "smart" cells and gene therapyYi Mai Meng broke the news in December, Senti Bio also announced the preclinical results of another logic-gated allogeneic CAR-NK cell therapy SENTI-202 at the annual meeting of the American Society of Hematology (ASH)
.
SENTI-202 is used for the potential treatment of acute myeloid leukemia (AML), which can more precisely target and eliminate cancer cells while preserving healthy tissue
.
"Existing cancer therapies usually only target a single tumor-associated antigen, which means that they can only be used safely and effectively if the antigen is expressed on tumor cells
.
"Senti Bio R&D Deputy Director Dr.
Alba Gonzalez said, "The exciting thing about our'logic gate' technology platform is that it has the potential to advance a very novel CAR-NK-based treatment method that can be more precise Treating a variety of solid tumors, while reducing the risk of targeted, non-tumor toxicity, which may increase the treatment window and provide patients with meaningful benefits
.
"▲Gene circuit applied to cell and gene therapy (picture source: Senti Bio) Recommended reading: Create a "smarter" CAR-NK, Lu Guanda's star company announced its listingYi Mai Meng broke the news reference materials: 1.
https://
