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▎The editor of WuXi AppTec’s content team today published an interesting study in the sub-issue of Nature Biomedical Engineering: Professor Gu Zhen’s team from Zhejiang University developed a The "cell reservoir" (cell reservoir) immune cell local slow and controlled release technology has verified in animal models that this technology can significantly enhance the efficacy of CAR-T cells against solid tumors.
Surgery for recurrence of solid tumors after surgery is the main choice for modern clinical treatment of tumor patients, but postoperative tumor recurrence and tumor metastasis are still the main causes of death of cancer patients.
In the surgical resection of solid tumors, due to the lack of precise imaging technology navigation, clinicians usually remove tissues that are larger than the actual tumor volume.
Even so, because many tumor cells are highly invasive and aggressive, it is difficult to completely remove all tumor cells with surgery.
Even with adjuvant chemotherapy or radiotherapy and other treatments, these residual cancer cells will still come back after surgery.
In recent years, tumor immunotherapy has become an effective means of clinical tumor treatment and has achieved exciting therapeutic effects.
As a "star" therapy, CAR-T cells have achieved great success in the treatment of hematological tumors.
The US FDA has approved five CAR-T cell therapies for the treatment of blood and multiple myeloma such as B-cell lymphoma.
However, CAR-T cell therapy has encountered many setbacks in the treatment of solid tumors.
This is largely due to the physical barrier of solid tumors and the immunosuppressive properties of the tumor microenvironment, which inhibit the activity and survival rate of CAR-T cells.
.Implantable "Cell Depot" Is there any way to maintain the activity of CAR-T cells in the tumor microenvironment and exert the ability of CAR-T cells to kill solid tumors? Many previous studies have pointed out that CAR-T cells injected directly into the tumor site in batches will quickly lose their activity and die.
At the same time, in addition to the tumor immunosuppressive microenvironment, tumor cells themselves can also escape the recognition function of T cells and inhibit their killing ability through the immune checkpoint suppression pathway.
Based on this idea, the researchers designed a “cell warehouse”-based local slow and controlled release technology of cells, which combines two different types of cells (CAR-T cells and anti-PD-L1 antibody-modified platelets) and encapsulated IL- 15 cytokine nanoparticles are loaded into an implantable hydrogel with good biocompatibility at the same time, and the controlled release of CAR-T cells can be achieved through the slow-release ability of the hydrogel to avoid CAR-T cells caused by rapid release T cells are largely inactivated, and the activity of CAR-T cells is maintained through the action of IL-15.
At the same time, in the postoperative inflammatory environment, platelets modified with PD-L1 antibodies can be activated and release anti-PD-L1 antibodies, blocking the immune checkpoint inhibition pathway, and enhancing the killing ability of CAR-T cells, which can be more effective Effectively suppress the recurrence of cancer after surgery.
▲"Cell Warehouse" delivery system.
CAR-T cells (yellow) and platelets (purple red) linked to anti-PD-L1 antibodies are loaded in a highly biocompatible hyaluronic acid hydrogel (blue) (image source: provided by the research author).
The researchers will It is called "cell warehouse" and serves as a local slow and controlled release of cells.
This is after the "combined cell drug delivery" treatment of acute myeloid leukemia in 2018, Gu Zhen's team once again used the cell combination strategy for tumor immunotherapy.
"Clinically, the combined use of two or more drugs can effectively improve drug efficacy, prevent drug resistance, reduce toxic side effects, etc.
; in recent years, we have been very interested in the combined use of different cellular drugs to increase efficacy and reduce toxicity.
" The co-corresponding author of the study, said Dr.
Gu Zhen, a professor at the School of Pharmacy of Zhejiang University and the Run Run Run Run Hospital. "This local cell slow and controlled release strategy can maximize the synergistic therapeutic effect of two different cells at the same time.
CAR-T cells can stimulate tumor cells to express more PD-L1 and enhance the effect of anti-PD-L1 antibody-platelets.
At the same time, the modified platelets can inhibit the immune checkpoint pathway and enhance the lethality of CAR-T cells through the release of anti-PD-L1 antibodies.
" The first author of this study, Dr.
Hu Quanyin, Assistant Professor, School of Pharmacy, University of Wisconsin-Madison, added Tao.
Cells cooperate to inhibit postoperative tumor recurrence.
In mouse experiments, the anti-postoperative tumor recurrence of this cell delivery technology has been verified.
Researchers first established a human melanoma tumor model under the skin, and then performed surgical resection after the tumor had grown to a certain size, simulating the surgical treatment of clinical tumors.
Subsequently, a hydrogel loaded with two types of cells was implanted at the tumor resection site to observe the therapeutic effect of this cell delivery strategy.
In addition, the researchers designed different control treatment groups, including physiological saline, direct injection of CAR-T cells and anti-PD-L1 antibody-platelets, and a hydrogel loaded with one cell.
After 3 weeks of treatment, the recurrence of cancer foci in mice was significantly suppressed after surgery.
In multiple control experiments, the tumor could not be effectively suppressed, and recurrence occurred.
It is worth noting that tracking the tumors treated by this cell combined drug delivery group, the tumor fluorescence intensity is only 1/60 of the normal saline group, showing a good tumor suppressing effect.
At the same time, the researchers also verified the proliferation ability of CAR-T cells at the tumor site after surgery.
The results showed that CAR-T cells delivered using "cell warehouse" showed good proliferation ability, but the CAR-T control group injected directly It quickly loses vitality and died.
At the same time, this local CAR-T delivery strategy has the effect of inhibiting distant tumors.
In the two-position tumor model constructed by the researchers, the tumor on one side was treated after surgery, and the tumor on the other side also showed a reduction in size, which proved that the locally delivered CAR-T cells also gathered in the distal tumor.
It provides the possibility of suppressing postoperative tumor metastasis. Summary In this study, a delivery strategy of "cell warehouse slow and controlled release" was used to load platelets linked to CAR-T cells and anti-PD-L1 antibodies in a hydrogel, and then slowly release CAR-T cells and block immune inspection.
The point pathway enhances the lethality of CAR-T cells on tumors, and has a good therapeutic effect on inhibiting cancer recurrence after surgery.
The researchers pointed out that on the one hand, this can also be used in combination with other therapies (such as chemotherapy and radiotherapy) to better inhibit tumor recurrence and metastasis; at the same time, new cell delivery strategies also provide new ideas for the treatment of other cell therapies and related diseases.
Reference: [1] Quanyin Hu et al.
, (2021).
Inhibition of post-surgery tumor recurrence via a hydrogel releasing CAR-T cells and anti-PD-L1-conjugated platelet.
Nature Biomedical Engineering.
Doi: 10.
1038/s41551 -021-00712-1
Surgery for recurrence of solid tumors after surgery is the main choice for modern clinical treatment of tumor patients, but postoperative tumor recurrence and tumor metastasis are still the main causes of death of cancer patients.
In the surgical resection of solid tumors, due to the lack of precise imaging technology navigation, clinicians usually remove tissues that are larger than the actual tumor volume.
Even so, because many tumor cells are highly invasive and aggressive, it is difficult to completely remove all tumor cells with surgery.
Even with adjuvant chemotherapy or radiotherapy and other treatments, these residual cancer cells will still come back after surgery.
In recent years, tumor immunotherapy has become an effective means of clinical tumor treatment and has achieved exciting therapeutic effects.
As a "star" therapy, CAR-T cells have achieved great success in the treatment of hematological tumors.
The US FDA has approved five CAR-T cell therapies for the treatment of blood and multiple myeloma such as B-cell lymphoma.
However, CAR-T cell therapy has encountered many setbacks in the treatment of solid tumors.
This is largely due to the physical barrier of solid tumors and the immunosuppressive properties of the tumor microenvironment, which inhibit the activity and survival rate of CAR-T cells.
.Implantable "Cell Depot" Is there any way to maintain the activity of CAR-T cells in the tumor microenvironment and exert the ability of CAR-T cells to kill solid tumors? Many previous studies have pointed out that CAR-T cells injected directly into the tumor site in batches will quickly lose their activity and die.
At the same time, in addition to the tumor immunosuppressive microenvironment, tumor cells themselves can also escape the recognition function of T cells and inhibit their killing ability through the immune checkpoint suppression pathway.
Based on this idea, the researchers designed a “cell warehouse”-based local slow and controlled release technology of cells, which combines two different types of cells (CAR-T cells and anti-PD-L1 antibody-modified platelets) and encapsulated IL- 15 cytokine nanoparticles are loaded into an implantable hydrogel with good biocompatibility at the same time, and the controlled release of CAR-T cells can be achieved through the slow-release ability of the hydrogel to avoid CAR-T cells caused by rapid release T cells are largely inactivated, and the activity of CAR-T cells is maintained through the action of IL-15.
At the same time, in the postoperative inflammatory environment, platelets modified with PD-L1 antibodies can be activated and release anti-PD-L1 antibodies, blocking the immune checkpoint inhibition pathway, and enhancing the killing ability of CAR-T cells, which can be more effective Effectively suppress the recurrence of cancer after surgery.
▲"Cell Warehouse" delivery system.
CAR-T cells (yellow) and platelets (purple red) linked to anti-PD-L1 antibodies are loaded in a highly biocompatible hyaluronic acid hydrogel (blue) (image source: provided by the research author).
The researchers will It is called "cell warehouse" and serves as a local slow and controlled release of cells.
This is after the "combined cell drug delivery" treatment of acute myeloid leukemia in 2018, Gu Zhen's team once again used the cell combination strategy for tumor immunotherapy.
"Clinically, the combined use of two or more drugs can effectively improve drug efficacy, prevent drug resistance, reduce toxic side effects, etc.
; in recent years, we have been very interested in the combined use of different cellular drugs to increase efficacy and reduce toxicity.
" The co-corresponding author of the study, said Dr.
Gu Zhen, a professor at the School of Pharmacy of Zhejiang University and the Run Run Run Run Hospital. "This local cell slow and controlled release strategy can maximize the synergistic therapeutic effect of two different cells at the same time.
CAR-T cells can stimulate tumor cells to express more PD-L1 and enhance the effect of anti-PD-L1 antibody-platelets.
At the same time, the modified platelets can inhibit the immune checkpoint pathway and enhance the lethality of CAR-T cells through the release of anti-PD-L1 antibodies.
" The first author of this study, Dr.
Hu Quanyin, Assistant Professor, School of Pharmacy, University of Wisconsin-Madison, added Tao.
Cells cooperate to inhibit postoperative tumor recurrence.
In mouse experiments, the anti-postoperative tumor recurrence of this cell delivery technology has been verified.
Researchers first established a human melanoma tumor model under the skin, and then performed surgical resection after the tumor had grown to a certain size, simulating the surgical treatment of clinical tumors.
Subsequently, a hydrogel loaded with two types of cells was implanted at the tumor resection site to observe the therapeutic effect of this cell delivery strategy.
In addition, the researchers designed different control treatment groups, including physiological saline, direct injection of CAR-T cells and anti-PD-L1 antibody-platelets, and a hydrogel loaded with one cell.
After 3 weeks of treatment, the recurrence of cancer foci in mice was significantly suppressed after surgery.
In multiple control experiments, the tumor could not be effectively suppressed, and recurrence occurred.
It is worth noting that tracking the tumors treated by this cell combined drug delivery group, the tumor fluorescence intensity is only 1/60 of the normal saline group, showing a good tumor suppressing effect.
At the same time, the researchers also verified the proliferation ability of CAR-T cells at the tumor site after surgery.
The results showed that CAR-T cells delivered using "cell warehouse" showed good proliferation ability, but the CAR-T control group injected directly It quickly loses vitality and died.
At the same time, this local CAR-T delivery strategy has the effect of inhibiting distant tumors.
In the two-position tumor model constructed by the researchers, the tumor on one side was treated after surgery, and the tumor on the other side also showed a reduction in size, which proved that the locally delivered CAR-T cells also gathered in the distal tumor.
It provides the possibility of suppressing postoperative tumor metastasis. Summary In this study, a delivery strategy of "cell warehouse slow and controlled release" was used to load platelets linked to CAR-T cells and anti-PD-L1 antibodies in a hydrogel, and then slowly release CAR-T cells and block immune inspection.
The point pathway enhances the lethality of CAR-T cells on tumors, and has a good therapeutic effect on inhibiting cancer recurrence after surgery.
The researchers pointed out that on the one hand, this can also be used in combination with other therapies (such as chemotherapy and radiotherapy) to better inhibit tumor recurrence and metastasis; at the same time, new cell delivery strategies also provide new ideas for the treatment of other cell therapies and related diseases.
Reference: [1] Quanyin Hu et al.
, (2021).
Inhibition of post-surgery tumor recurrence via a hydrogel releasing CAR-T cells and anti-PD-L1-conjugated platelet.
Nature Biomedical Engineering.
Doi: 10.
1038/s41551 -021-00712-1
