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▎The content team editor of WuXi AppTec's CAR-T cell therapy is one of the major breakthroughs in the field of cancer treatment in recent years.
So far, the US FDA has approved 5 CAR-T therapies for the treatment of various types of blood cancers.
However, in the treatment of solid tumors, there is still no approved CAR-T therapy.
So, what challenges does CAR-T therapy encounter in the treatment of solid tumors that are different from those in the treatment of blood cancers? What strategies are scientists using to overcome these challenges?
Recently, Nature Reviews Drug Discovery published an in-depth analysis of the challenges and solutions encountered in the treatment of solid tumors with CAR-T therapy.
Today, WuXi AppTec's content team will introduce the exciting content of this review in conjunction with public information.
Choosing the appropriate target for CAR-T cell therapy For CAR-T therapy, the appropriate target is the main reason for determining their efficacy and safety.
Because the chimeric antigen receptor (CAR) expressed on the surface of CAR-T cells will guide the cells to cells expressing target antigens, if these targets are expressed on healthy tissues, then CAR-T therapy may even be combined with the correct target.
Because it kills healthy cells, it produces strong toxic side effects.
Currently approved CAR-T therapies for the treatment of hematological cancers all target specific antigens on B lymphocytes (such as CD19 and B cell maturation antigens), and a common side effect of these therapies is the elimination of healthy B cells.
It is one of the known side effects of these CAR-T therapies, but they still have acceptable safety.
In the treatment of solid tumors, it is very difficult to find a specific target that is only expressed in tumors but not in healthy tissues.
Nature Reviews Drug Discovery’s review article pointed out that CAR-T therapies targeting multiple different targets have had serious side effects in clinical trials.
▲CAR-T therapy has experienced toxic side effects due to the binding of targets expressed in non-tumor tissues in clinical trials (picture source: reference [1]) Therefore, when treating solid tumors, choose a more specific target The point is crucial.
At present, in the treatment of solid tumors, the "hot" targets targeted by cell therapy under investigation include HER2, EGFR, mesothelin, NY-ESO-1, PSMA and so on.
Among them, NY-ESO-1 belongs to the cancer testis antigen (CTA), which is usually only expressed in testis or ovarian tissue, but in many cancers, this antigen will start to express again.
Therefore, it provides a target antigen with strong specificity but weak side effects for T cell therapy.
In addition to finding highly specific targets, another way to improve the specificity of CAR-T therapy is to modify the receptors expressed by CAR-T cells to enhance their ability to recognize tumor cells.
For example, in a study that recently appeared on the cover of Science Translational Medicine.
Researchers at the University of California, San Francisco (UCSF) designed a "smart" CAR-T cell.
Using a gene expression regulation system called synNotch, first guide CAR-T cells to recognize EGFRvIII, which is highly specifically expressed in some cancer cells, and then stimulate the expression of CAR that recognizes EphA2 or IL13Rα2.
These two proteins are expressed in all cancer cells, which can instruct T cells to destroy all cancer cells.
Although EphA2 or IL13Rα2 are also expressed in some healthy cells, the CAR that recognizes them is only expressed on T cells that migrate to the tumor under the regulation of the synNotch system, so healthy cells will not be affected by these CAR-T cells.
attack. ▲The design and mechanism of smart CAR-T cell therapy, through the synNotch system that binds to specific antigens, regulates the expression of CAR that recognizes surrounding cancer cells (picture source: reference [4]) This design may also solve CAR-T therapy Another challenge in solid tumors is that due to its heterogeneity, not all cells express the targets targeted by CAR-T therapy.
The effect of this synNotch system is called the "bystander effect".
It means that after CAR-T cells specifically reach the tumor, they can kill surrounding tumor cells that do not express specific targets, thereby enhancing the killing effect.
In the mouse model, the "smart" CAR-T therapy designed with the synNotch system has indeed shown better results.
▲In the mouse tumor model, CAR-T cells implanted with the synNotch system (left picture) showed stronger anti-cancer ability (picture source: reference [4]) In addition to the synNotch system, scientists also designed A variety of other "molecular switches", their functions include allowing CAR-T cells to recognize a variety of different antigens; inactivating after recognizing antigens expressed by healthy cells; or regulating the activity of CAR-T cells through drugs.
These modifications to CAR-T cells all help to improve their specificity in the treatment of solid tumors and reduce toxic side effects.
Overcoming the tumor microenvironment of immunosuppressive solid tumors Compared with hematological cancers, an important difference is the tumor microenvironment (TME) formed around the solid tumor.
The tumor microenvironment contains a variety of immunosuppressive cells, such as regulatory T cells (Treg), tumor-associated macrophages (TAM), and so on.
The tumor microenvironment also overexpresses TGFβ, IL-10, IL-4 and other immunosuppressive cytokines.
The immunosuppressive environment constituted by these factors can significantly reduce the effectiveness of CAR-T cells.
▲A variety of factors in the tumor microenvironment of solid tumors that may affect the efficacy of CAR-T cells (picture source: reference [1]) In order to overcome the impact of the tumor microenvironment, scientists have added a new generation of CAR-T therapies "Weapon" against immunosuppression.
These "armed CAR-T cells" (armored CAR-T cells) are becoming a trend in the development of T cell therapy.
The "weapons" that scientists have added to CAR-T cells are diverse.
For example, one way to combat the immunosuppressive function of TGFβ is to express a dominant negative receptor (DNR) in CAR-T cells that can block TGFβ signaling.
This DNR can compete with the TGFβ receptor originally present in the cell and bind to TGFβ, but it will not trigger the next signal transduction after binding to TGFβ.
A new generation of CAR-T therapy developed by Tmunity, co-founded by Dr.
Carl June, a well-known CAR-T therapy pioneer, adopts the strategy of expressing DNR that blocks the TGFβ signaling pathway.
This CAR-T therapy targeting PSMA has shown clinical activity in clinical trials for the treatment of prostate cancer patients.
This strategy can also be used to block PD-1 mediated immunosuppressive signaling pathways.
▲Multiple strategies for "arming" CAR-T therapy (picture source: reference [3]) Another way to combat the tumor microenvironment is to allow CAR-T cells to simultaneously express pro-inflammatory cytokines that can change the characteristics of the tumor microenvironment , Such as IL-12, IL-18 and IL-23.
IL-12 and IL-18 can increase the secretion of pro-inflammatory cytokine IFN-γ, and IFN-γ can further promote the release of IL-12 from macrophages, thereby creating a positive feedback loop.
Previous research results have shown that systemic use of IL-12 and IL-18 can cause strong toxicity.
If CAR-T cells continue to express these factors, they may also be toxic.
Therefore, the current design is to allow CAR-T cells to After binding to the target, it drives the expression of cytokines, thereby limiting the effect of cytokines to the vicinity of the tumor.
The popularity of CRISPR gene editing technology also provides a new tool for transforming CAR-T cell therapy.
Tmunity uses gene editing to knock out the endogenous T cell receptor (TCR) and PD-1 receptor in T cells, and then Then express the TCR targeting the NY-ESO-1 antigen.
The TCR cell therapy developed using this technology has shown positive effects in clinical trials.
CRISPR gene editing technology may not only help knock out genes that may affect the function of T cell therapy, but it can also be used as a screening tool to discover new unknown T cell function regulators.
Conclusion At present, scientists have a variety of tools to adjust the characteristics of CAR-T therapy to improve their specificity, controllability, safety, and efficacy.
The use of the latest cutting-edge technology to improve CAR-T therapy in many aspects is expected to overcome the multiple obstacles that need to be faced in the treatment of solid tumors.
On the other hand, in addition to CAR-T cell therapy, scientists are also developing other forms of immune cell therapy.
They include TCR cell therapy that can recognize antigens in tumor cells and CAR-M therapy that uses innate immune cells.
The development of tumor infiltrating lymphocyte (TIL) therapy by Iovance biotherapeutics has also shown positive effects in key clinical trials for the treatment of patients with advanced cervical cancer and melanoma.
We wish that progress in the field of immune cell therapy will overcome the challenges faced by solid tumors as soon as possible and benefit more patients.
Reference materials: [1] Hou et al.
(2021).
Navigating CAR- T cells through the solid- tumour microenvironment.
Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-021-00189-2[2 ] Researchers in biotech, academia and Big Pharma are offering puzzle pieces to crack CAR-T for solid tumors.
Will they ever snap together? Retrieved May 25, 2021, from https://endpts.
com/researchers-in-biotech-academia -and-big-pharma-are-offering-puzzle-pieces-to-crack-car-t-for-solid-tumors-will-they-ever-snap-together/[3] Hawkins et al.
, (2021) .
Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy.
Biologics: Targets and Therapy, https://doi.
org/10.
2147/BTT.
S291768[4] Choe et al.
, (2021).
SynNotch- CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.
Science Translational Medicine, DOI:10.
1126/scitranslmed.
abe7378[5] Tmunity Corporate Presentation.
Retrieved May 25, 2021, from https://ea68ab67-ef93-4814-a431-d4276b866a62.
filesusr.
com/ugd/233d22_2231a96a695e45deb71245baa7a7009d.
pdf Note: This article aims to introduce medical and health research progress, not Recommended treatment plan. If you need guidance on the treatment plan, please go to a regular hospital for treatment.
So far, the US FDA has approved 5 CAR-T therapies for the treatment of various types of blood cancers.
However, in the treatment of solid tumors, there is still no approved CAR-T therapy.
So, what challenges does CAR-T therapy encounter in the treatment of solid tumors that are different from those in the treatment of blood cancers? What strategies are scientists using to overcome these challenges?
Recently, Nature Reviews Drug Discovery published an in-depth analysis of the challenges and solutions encountered in the treatment of solid tumors with CAR-T therapy.
Today, WuXi AppTec's content team will introduce the exciting content of this review in conjunction with public information.
Choosing the appropriate target for CAR-T cell therapy For CAR-T therapy, the appropriate target is the main reason for determining their efficacy and safety.
Because the chimeric antigen receptor (CAR) expressed on the surface of CAR-T cells will guide the cells to cells expressing target antigens, if these targets are expressed on healthy tissues, then CAR-T therapy may even be combined with the correct target.
Because it kills healthy cells, it produces strong toxic side effects.
Currently approved CAR-T therapies for the treatment of hematological cancers all target specific antigens on B lymphocytes (such as CD19 and B cell maturation antigens), and a common side effect of these therapies is the elimination of healthy B cells.
It is one of the known side effects of these CAR-T therapies, but they still have acceptable safety.
In the treatment of solid tumors, it is very difficult to find a specific target that is only expressed in tumors but not in healthy tissues.
Nature Reviews Drug Discovery’s review article pointed out that CAR-T therapies targeting multiple different targets have had serious side effects in clinical trials.
▲CAR-T therapy has experienced toxic side effects due to the binding of targets expressed in non-tumor tissues in clinical trials (picture source: reference [1]) Therefore, when treating solid tumors, choose a more specific target The point is crucial.
At present, in the treatment of solid tumors, the "hot" targets targeted by cell therapy under investigation include HER2, EGFR, mesothelin, NY-ESO-1, PSMA and so on.
Among them, NY-ESO-1 belongs to the cancer testis antigen (CTA), which is usually only expressed in testis or ovarian tissue, but in many cancers, this antigen will start to express again.
Therefore, it provides a target antigen with strong specificity but weak side effects for T cell therapy.
In addition to finding highly specific targets, another way to improve the specificity of CAR-T therapy is to modify the receptors expressed by CAR-T cells to enhance their ability to recognize tumor cells.
For example, in a study that recently appeared on the cover of Science Translational Medicine.
Researchers at the University of California, San Francisco (UCSF) designed a "smart" CAR-T cell.
Using a gene expression regulation system called synNotch, first guide CAR-T cells to recognize EGFRvIII, which is highly specifically expressed in some cancer cells, and then stimulate the expression of CAR that recognizes EphA2 or IL13Rα2.
These two proteins are expressed in all cancer cells, which can instruct T cells to destroy all cancer cells.
Although EphA2 or IL13Rα2 are also expressed in some healthy cells, the CAR that recognizes them is only expressed on T cells that migrate to the tumor under the regulation of the synNotch system, so healthy cells will not be affected by these CAR-T cells.
attack. ▲The design and mechanism of smart CAR-T cell therapy, through the synNotch system that binds to specific antigens, regulates the expression of CAR that recognizes surrounding cancer cells (picture source: reference [4]) This design may also solve CAR-T therapy Another challenge in solid tumors is that due to its heterogeneity, not all cells express the targets targeted by CAR-T therapy.
The effect of this synNotch system is called the "bystander effect".
It means that after CAR-T cells specifically reach the tumor, they can kill surrounding tumor cells that do not express specific targets, thereby enhancing the killing effect.
In the mouse model, the "smart" CAR-T therapy designed with the synNotch system has indeed shown better results.
▲In the mouse tumor model, CAR-T cells implanted with the synNotch system (left picture) showed stronger anti-cancer ability (picture source: reference [4]) In addition to the synNotch system, scientists also designed A variety of other "molecular switches", their functions include allowing CAR-T cells to recognize a variety of different antigens; inactivating after recognizing antigens expressed by healthy cells; or regulating the activity of CAR-T cells through drugs.
These modifications to CAR-T cells all help to improve their specificity in the treatment of solid tumors and reduce toxic side effects.
Overcoming the tumor microenvironment of immunosuppressive solid tumors Compared with hematological cancers, an important difference is the tumor microenvironment (TME) formed around the solid tumor.
The tumor microenvironment contains a variety of immunosuppressive cells, such as regulatory T cells (Treg), tumor-associated macrophages (TAM), and so on.
The tumor microenvironment also overexpresses TGFβ, IL-10, IL-4 and other immunosuppressive cytokines.
The immunosuppressive environment constituted by these factors can significantly reduce the effectiveness of CAR-T cells.
▲A variety of factors in the tumor microenvironment of solid tumors that may affect the efficacy of CAR-T cells (picture source: reference [1]) In order to overcome the impact of the tumor microenvironment, scientists have added a new generation of CAR-T therapies "Weapon" against immunosuppression.
These "armed CAR-T cells" (armored CAR-T cells) are becoming a trend in the development of T cell therapy.
The "weapons" that scientists have added to CAR-T cells are diverse.
For example, one way to combat the immunosuppressive function of TGFβ is to express a dominant negative receptor (DNR) in CAR-T cells that can block TGFβ signaling.
This DNR can compete with the TGFβ receptor originally present in the cell and bind to TGFβ, but it will not trigger the next signal transduction after binding to TGFβ.
A new generation of CAR-T therapy developed by Tmunity, co-founded by Dr.
Carl June, a well-known CAR-T therapy pioneer, adopts the strategy of expressing DNR that blocks the TGFβ signaling pathway.
This CAR-T therapy targeting PSMA has shown clinical activity in clinical trials for the treatment of prostate cancer patients.
This strategy can also be used to block PD-1 mediated immunosuppressive signaling pathways.
▲Multiple strategies for "arming" CAR-T therapy (picture source: reference [3]) Another way to combat the tumor microenvironment is to allow CAR-T cells to simultaneously express pro-inflammatory cytokines that can change the characteristics of the tumor microenvironment , Such as IL-12, IL-18 and IL-23.
IL-12 and IL-18 can increase the secretion of pro-inflammatory cytokine IFN-γ, and IFN-γ can further promote the release of IL-12 from macrophages, thereby creating a positive feedback loop.
Previous research results have shown that systemic use of IL-12 and IL-18 can cause strong toxicity.
If CAR-T cells continue to express these factors, they may also be toxic.
Therefore, the current design is to allow CAR-T cells to After binding to the target, it drives the expression of cytokines, thereby limiting the effect of cytokines to the vicinity of the tumor.
The popularity of CRISPR gene editing technology also provides a new tool for transforming CAR-T cell therapy.
Tmunity uses gene editing to knock out the endogenous T cell receptor (TCR) and PD-1 receptor in T cells, and then Then express the TCR targeting the NY-ESO-1 antigen.
The TCR cell therapy developed using this technology has shown positive effects in clinical trials.
CRISPR gene editing technology may not only help knock out genes that may affect the function of T cell therapy, but it can also be used as a screening tool to discover new unknown T cell function regulators.
Conclusion At present, scientists have a variety of tools to adjust the characteristics of CAR-T therapy to improve their specificity, controllability, safety, and efficacy.
The use of the latest cutting-edge technology to improve CAR-T therapy in many aspects is expected to overcome the multiple obstacles that need to be faced in the treatment of solid tumors.
On the other hand, in addition to CAR-T cell therapy, scientists are also developing other forms of immune cell therapy.
They include TCR cell therapy that can recognize antigens in tumor cells and CAR-M therapy that uses innate immune cells.
The development of tumor infiltrating lymphocyte (TIL) therapy by Iovance biotherapeutics has also shown positive effects in key clinical trials for the treatment of patients with advanced cervical cancer and melanoma.
We wish that progress in the field of immune cell therapy will overcome the challenges faced by solid tumors as soon as possible and benefit more patients.
Reference materials: [1] Hou et al.
(2021).
Navigating CAR- T cells through the solid- tumour microenvironment.
Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-021-00189-2[2 ] Researchers in biotech, academia and Big Pharma are offering puzzle pieces to crack CAR-T for solid tumors.
Will they ever snap together? Retrieved May 25, 2021, from https://endpts.
com/researchers-in-biotech-academia -and-big-pharma-are-offering-puzzle-pieces-to-crack-car-t-for-solid-tumors-will-they-ever-snap-together/[3] Hawkins et al.
, (2021) .
Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy.
Biologics: Targets and Therapy, https://doi.
org/10.
2147/BTT.
S291768[4] Choe et al.
, (2021).
SynNotch- CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.
Science Translational Medicine, DOI:10.
1126/scitranslmed.
abe7378[5] Tmunity Corporate Presentation.
Retrieved May 25, 2021, from https://ea68ab67-ef93-4814-a431-d4276b866a62.
filesusr.
com/ugd/233d22_2231a96a695e45deb71245baa7a7009d.
pdf Note: This article aims to introduce medical and health research progress, not Recommended treatment plan. If you need guidance on the treatment plan, please go to a regular hospital for treatment.
