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▎The content team of WuXi AppTec edited T cells expressing chimeric antigen receptor (CAR, chimeric antigen receptor) (CAR-T therapy) is one of the major breakthroughs in the field of cancer treatment in recent years, and it has achieved excellent efficacy in the treatment of hematological cancers.
.
CAR is like equipping T cells with a "GPS navigation system", allowing T cells to quickly locate tumor cells that are good at camouflage, so as to find and kill them.
Recently, "Nature-Medical" published a study.
Researchers at the University of Pennsylvania School of Medicine (Penn Medicine) found that when T cells are equipped with CAR, the structure can be better activated by making subtle "simplification" of the structure.
, It has been shown in pre-clinical studies that the treatment effect can be greatly improved.
1.
The first CAR-T therapy-CD19 antigen target CD19 is a unique target for B cells.
Kymriah, which targets the CD19 antigen developed by the University of Pennsylvania School of Medicine in cooperation with Novartis, became the first to receive the US FDA The approved CAR-T therapy is used to treat children and young patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL, acute lymphoblastic leukemia).
However, long-term follow-up showed that some of the patients in remission eventually relapsed.
It is possible that the tumor cells have lost the CD19 antigen and thus escaped the tracking and attack of CD19 CAR-T therapy.
2.
A new generation of CAR-T therapy-CD22 antigen targets Researchers have developed a second method for patients who have relapsed: CAR-T therapy targeting CD22 antigen.
CD22 is also a highly expressed target on the surface of B cells.
However, two preliminary clinical studies showed that the overall clinical response was much lower than expected.
In contrast, similar trials conducted by the National Cancer Institute (NCI) have yielded positive results.
Why are the results so different when using the same target? The research team went back to analyze the structure of the CAR and found that the only difference between the two CARs is the length of the linker that connects the two antibody single-chain variable region fragments.
The length of the linker in NCI's CAR is 5 amino acids (the green part in the figure below), while the linker used by the University of Pennsylvania team is 20 amino acids in length (the blue part in the figure below).
So is the difference between these 15 amino acids the key to the difference in therapy? 3.
Less is more, shorter CAR structure ▲Illustration of long CAR22 and short CAR22 structures (picture source: reference [2]) Based on this discovery, the research team then cooperated with Novartis to construct a new target To CD22 CAR-T cells, it has a shorter linker.
The results of comparison experiments between new CAR-T cells and previously constructed CAR-T cells show that CAR-T cells with shorter linkers can activate T cells without binding to antigen.
"This discovery completely overturns the current theory.
" Co-corresponding author Professor Saar I.
Gill said.
Usually this may lead to premature exhaustion of T cells, but in CAR-T cells carrying the 4-1BB costimulatory domain, this pre-activation actually improves the cell's killing ability and anti-tumor activity against B cells.
Co-corresponding author Professor Marco Ruella pointed out: "Some small differences in amino acids will have a huge impact on patients.
When we shorten the linker by 15 amino acids, the two antibody variable region fragments will more easily stick together and be activated in advance.
CAR-T cells.
"The research team is conducting a new clinical trial for adults and children with refractory/relapsed ALL to study the clinical effects of short linker CAR-T cells.
At the same time, research to analyze the importance of linker length to other CAR-T cells is also underway.
"Even simple molecular changes may have a huge impact on the function of synthesized CAR-T cells.
The
most exciting thing is that these data reveal an unprecedented improvement in CAR-T therapy.
Way.
" said Dr.
Nathan Singh, the first author of this article.
Source of title image: 123RF Reference material: [1] Less is more for the next generation of CAR T cells.
Retrieved April 22, 2021, from php[2] Singh, N.
et al.
(2021).
Antigen-independent activation enhances the efficacy of 4–1BB-costimulated CD22 CAR T cells.
Nature Medicine.
021-01326-5
.
CAR is like equipping T cells with a "GPS navigation system", allowing T cells to quickly locate tumor cells that are good at camouflage, so as to find and kill them.
Recently, "Nature-Medical" published a study.
Researchers at the University of Pennsylvania School of Medicine (Penn Medicine) found that when T cells are equipped with CAR, the structure can be better activated by making subtle "simplification" of the structure.
, It has been shown in pre-clinical studies that the treatment effect can be greatly improved.
1.
The first CAR-T therapy-CD19 antigen target CD19 is a unique target for B cells.
Kymriah, which targets the CD19 antigen developed by the University of Pennsylvania School of Medicine in cooperation with Novartis, became the first to receive the US FDA The approved CAR-T therapy is used to treat children and young patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL, acute lymphoblastic leukemia).
However, long-term follow-up showed that some of the patients in remission eventually relapsed.
It is possible that the tumor cells have lost the CD19 antigen and thus escaped the tracking and attack of CD19 CAR-T therapy.
2.
A new generation of CAR-T therapy-CD22 antigen targets Researchers have developed a second method for patients who have relapsed: CAR-T therapy targeting CD22 antigen.
CD22 is also a highly expressed target on the surface of B cells.
However, two preliminary clinical studies showed that the overall clinical response was much lower than expected.
In contrast, similar trials conducted by the National Cancer Institute (NCI) have yielded positive results.
Why are the results so different when using the same target? The research team went back to analyze the structure of the CAR and found that the only difference between the two CARs is the length of the linker that connects the two antibody single-chain variable region fragments.
The length of the linker in NCI's CAR is 5 amino acids (the green part in the figure below), while the linker used by the University of Pennsylvania team is 20 amino acids in length (the blue part in the figure below).
So is the difference between these 15 amino acids the key to the difference in therapy? 3.
Less is more, shorter CAR structure ▲Illustration of long CAR22 and short CAR22 structures (picture source: reference [2]) Based on this discovery, the research team then cooperated with Novartis to construct a new target To CD22 CAR-T cells, it has a shorter linker.
The results of comparison experiments between new CAR-T cells and previously constructed CAR-T cells show that CAR-T cells with shorter linkers can activate T cells without binding to antigen.
"This discovery completely overturns the current theory.
" Co-corresponding author Professor Saar I.
Gill said.
Usually this may lead to premature exhaustion of T cells, but in CAR-T cells carrying the 4-1BB costimulatory domain, this pre-activation actually improves the cell's killing ability and anti-tumor activity against B cells.
Co-corresponding author Professor Marco Ruella pointed out: "Some small differences in amino acids will have a huge impact on patients.
When we shorten the linker by 15 amino acids, the two antibody variable region fragments will more easily stick together and be activated in advance.
CAR-T cells.
"The research team is conducting a new clinical trial for adults and children with refractory/relapsed ALL to study the clinical effects of short linker CAR-T cells.
At the same time, research to analyze the importance of linker length to other CAR-T cells is also underway.
"Even simple molecular changes may have a huge impact on the function of synthesized CAR-T cells.
The
most exciting thing is that these data reveal an unprecedented improvement in CAR-T therapy.
Way.
" said Dr.
Nathan Singh, the first author of this article.
Source of title image: 123RF Reference material: [1] Less is more for the next generation of CAR T cells.
Retrieved April 22, 2021, from php[2] Singh, N.
et al.
(2021).
Antigen-independent activation enhances the efficacy of 4–1BB-costimulated CD22 CAR T cells.
Nature Medicine.
021-01326-5
