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← Skip left and right to view, click [Read the original text] to learn more → The immunosuppressive signal in the tumor microenvironment, through the inhibitory receptor on the T cell, inhibits the anti-tumor T cell response, which is the traditional CAR-T solid tumor curative effect One of the bad factors
.
Use "inhibitory-to-stimulatory" (Inhibitory-to-stimulatory, ITS) chimeric receptor, the extracellular segment uses the extracellular segment of the inhibitory receptor, and the intracellular segment uses the intracellular segment of the stimulatory receptor.
It binds to inhibitory ligands (such as PD-L1), but intracellular signal transduction stimulus signals (such as CD28) is a strategy to destroy the inhibitory tumor microenvironment
.
Immune checkpoint-CD28 chimeric receptor PD-1: CD28 chimeric receptor PD1 is an inhibitory receptor for T cell exhaustion in TME
.
Fusion of the extracellular domain of PD-1 with the stimulating intracellular domain of other molecules (especially CD28) can convert the inhibitory signal of PD-1 into a stimulating signal
.
In vitro, the PD1:CD28 chimeric molecule has been shown to respond to tumor cells expressing PD-L1 and transduce activation signals through the chimeric receptor to enhance the proliferation, cytokine production and cytotoxicity of CD8+ T cells
.
In a xenograft mouse model, it was found that the PD1:CD28 chimeric receptor can be used with different CARs to enhance CAR-T cell activity, including tumor killing, cytokine secretion, tumor infiltration and expansion, and downregulation of PD1 and TIM3, etc.
.
Clinical research NCT03258047 Novel Autologou CAR-T Therapy for Relapsed/Refractory B Cell Lymphoma Research unit: The second hospital of Zhejiang University Clinical research results published in Clin Cancer Res in 2021, 17 patients, 7 CR, 3 PR, 7 PD
.
Other PD-1: CD28 chimeric receptor T cell therapy clinical trials: NCT02930967, NCT02937844, NCT03258047
.
CTLA-4: CD28 chimeric receptor CTLA-4 is another important immune checkpoint, an important molecule that inhibits the function of immune cells in the tumor microenvironment
.
Similar to PD-1, CTLA-4: CD28 chimeric molecule CAR-T cells have also begun to have related research
.
In 2021, Front.
Immunol.
published the research results of Guangzhou Medical University and other units, showing that CTLA4-CD28-CD3z T cells have good anti-tumor activity in mouse models
.
However, no clinical trials have been found yet
.
TIGIT: CD28 chimeric receptor TIGIT (Vstm3) is an immunoglobulin superfamily, discovered in 2009
.
TIGHT belongs to the poliovirus receptor family, which also includes: PVR(CD155), CD96, CD112(PVRL2), CD112R(PVRIG), CD226(DNAM-1)
.
TIGIT, CD96, PVRIG and CD226 are expressed on T cells and NK cells, and CD155 and CD112 are expressed on DC cells and tumor cells
.
TIGIT is expressed in activated T cells and is a molecule that maintains the immune balance in the body
.
TIGIT is expressed in Treg and secretes IL-10 and Fgl2 to suppress immunity
.
In the tumor microenvironment, TIGIT is expressed in CD8 + TILS and a variety of tumor cells, as well as Treg
.
The research of TIGIT-28 is currently mainly in the laboratory stage and has not yet entered clinical practice
.
Some researchers compared TIGIT/28TMTIGIT (the transmembrane area of the extracellular segment of TIGIT plus the intracellular segment of CD28) and TIGIT/28TM28 (the extracellular segment of TIGIT plus the intracellular segment of the transmembrane area of CD28), and the former has better activity than the latter
.
CD200R: CD28 chimeric receptor CD200 is expressed on various types of tumor cells and binds to T cell CD200R to inhibit T cell activation
.
Oda et al.
compared chimera molecules with different transmembrane domains and handle region lengths, and the experimental results showed that CD200R-9aas-CD28cys is the best for T cell proliferation
.
This structure contains the extracellular domain of CD200 (AA1-229), which is fused to the AA142-218 region of CD28
.
CD28 membrane proximal cysteine (AA142) is integrated into this optimal receptor to promote disulfide bond-mediated homodimerization and enhance natural CD28 signal transduction
.
In the mouse leukemia model, the modified T cells showed a higher survival rate and the activity of controlling tumor growth
.
In phase 2 clinical trials (NCT01640301, NCT02408016), human CD200R-9aas-CD28cys receptor can also effectively enhance the proliferation of CD8+ T cells and is activated by human tumor cells expressing CD200 (Reference 5)
.
Cytokine chimeric receptors Several inhibitory cytokines and receptors inhibit the anti-tumor T cell response
.
The tumor microenvironment usually has a high level of IL-4, which promotes immune suppression by inducing the polarization of Th2 cells and M2 macrophages, while inhibiting the polarization of Th1 cells and the production of pro-inflammatory cytokines by antigen-presenting cells (APCs)
.
IL-4αβ switch receptor In order to inhibit the effects of IL-4, Wilkie et al.
developed a chimeric IL-4 receptor called 4αβ, which incorporates the extracellular domain of IL-4Rα (AA1-233).
To the transmembrane and extracellular domain of IL-2Rβ (AA241-551)
.
Transfer 4αβ and CAR into CTLL-2T cell line through SFG retroviral vector, and adding IL-4 can promote the proliferation of CTLL-2T cell line, and increase the secretion of IL-2 and IFN-γ, showing that the inhibitory signal is converted to Stimulus signal
.
IL-4/7 ICRMohammed et al.
produced a chimeric receptor called 4/7 inverted cytokine receptor (ICR), which contains the extracellular domain of IL-4Rα (AA1-233) And the transmembrane and intracellular domains of IL-7Rα (AA240-459)
.
When used alone, 4/7ICR cells can respond to IL-4 and promote T cell proliferation, but cannot induce anti-tumor activity
.
In xenograft tumor models in vitro and in humanized mice, the combination of 4/7 ICR and CAR can lead to antigen- and cytokine-dependent anti-tumor T cell responses
.
IL-4/21ICRWang et al.
developed a similar receptor 4/21ICR, which uses the IL-4Rα extradomain (AA1-233) and the transmembrane and intracellular domains of IL-21R (AA233-538)
.
In the presence of IL-4, CAR-T cells expressing IL-4/21 ICR differentiated into a Th17-like phenotype, and showed enhanced persistence and anti-tumor activity
.
The editor concludes that the poor inhibitory immune microenvironment of tumors is a key factor in the failure of CAR-T therapy to make significant progress in solid tumors
.
Based on this, scientists thought about converting inhibitory signals into stimulatory signals, resulting in ITS (inhibitory signal-to-stimulatory signal) chimeric receptor T cell therapy, which is different from the classic chimeric antigen receptor CAR-T therapy
.
Current research is mainly focused on immune checkpoints (PD-1, CTLA-4, etc.
) and inhibitory cytokines (IL-4, etc.
), most of which are still in the pre-clinical laboratory stage, PD-1: CD28 chimeric receptor The therapy has begun to enter the clinic and has made some progress
.
References 1.
Guo J, Kent A, Davila E.
Chimeric non-antigen receptors in T cell-based cancer therapy.
Journal for ImmunoTherapy of Cancer 2021;9:e002628.
doi:10.
1136/jitc-2021-0026282.
Hui Liu et al, CD19-Specific CAR-T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor is Effective in Patients with PD-L1 Positive B-Cell Lymphoma, Clin Cancer Res.
2021 Jan 15;27(2):473- 484.
3.
Lin S, Cheng L, Ye W, Li S, Zheng D, Qin L, Wu Q, Long Y, Lin S, Wang S, Huang G, Li P, Yao Y and Sun X (2021) Chimeric CTLA4-CD28 -CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86--Positive B Cell Malignancies.
Front.
Immunol.
12:642528.
4.
Hoogi S, Eisenberg V, Mayer S, et al.
A TIGIT-based chimeric costimulatory switch receptor improves T-cell anti -tumor function.
J Immunother Cancer 2019;7:2435.
Oda SK, Daman AW, Garcia NM, et al.
A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia.
Blood 2017;130:2410–96.
Wilkie S, Burbridge SE, Chiapero-Stanke L, et al.
Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4.
J Biol Chem.
2010;285(33):25538–25544.
doi:10.
1074/jbc.
M110.
12795178.
7.
Leen AM, Sukumaran S, Watanabe N, et al.
Reversal of tumor immune inhibition using a chimeric cytokine receptor.
Mol Ther.
2014;22(6):1211–1220.
doi:10.
1038/mt.
2014.
4779.
8.
Mohammed S, Sukumaran S, Bajgain P, et al.
Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer.
Mol Ther.
2017;25(1):249–258.
doi:10.
1016/j.
ymthe.
2016.
10.
01680.
9.
Wang Y, Jiang H, Luo H, et al.
An IL-4/21 inverted cytokine receptor improving CAR-T cell potency in immunosuppressive solid-tumor microenvironment.
Front Immunol.
2019;10:1691.
doi:10.
3389/fimmu.
2019.
016918110.
Babak Moghimi et al, Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma, Nat Commun.
2021 Jan 21;12(1):511.
.
Use "inhibitory-to-stimulatory" (Inhibitory-to-stimulatory, ITS) chimeric receptor, the extracellular segment uses the extracellular segment of the inhibitory receptor, and the intracellular segment uses the intracellular segment of the stimulatory receptor.
It binds to inhibitory ligands (such as PD-L1), but intracellular signal transduction stimulus signals (such as CD28) is a strategy to destroy the inhibitory tumor microenvironment
.
Immune checkpoint-CD28 chimeric receptor PD-1: CD28 chimeric receptor PD1 is an inhibitory receptor for T cell exhaustion in TME
.
Fusion of the extracellular domain of PD-1 with the stimulating intracellular domain of other molecules (especially CD28) can convert the inhibitory signal of PD-1 into a stimulating signal
.
In vitro, the PD1:CD28 chimeric molecule has been shown to respond to tumor cells expressing PD-L1 and transduce activation signals through the chimeric receptor to enhance the proliferation, cytokine production and cytotoxicity of CD8+ T cells
.
In a xenograft mouse model, it was found that the PD1:CD28 chimeric receptor can be used with different CARs to enhance CAR-T cell activity, including tumor killing, cytokine secretion, tumor infiltration and expansion, and downregulation of PD1 and TIM3, etc.
.
Clinical research NCT03258047 Novel Autologou CAR-T Therapy for Relapsed/Refractory B Cell Lymphoma Research unit: The second hospital of Zhejiang University Clinical research results published in Clin Cancer Res in 2021, 17 patients, 7 CR, 3 PR, 7 PD
.
Other PD-1: CD28 chimeric receptor T cell therapy clinical trials: NCT02930967, NCT02937844, NCT03258047
.
CTLA-4: CD28 chimeric receptor CTLA-4 is another important immune checkpoint, an important molecule that inhibits the function of immune cells in the tumor microenvironment
.
Similar to PD-1, CTLA-4: CD28 chimeric molecule CAR-T cells have also begun to have related research
.
In 2021, Front.
Immunol.
published the research results of Guangzhou Medical University and other units, showing that CTLA4-CD28-CD3z T cells have good anti-tumor activity in mouse models
.
However, no clinical trials have been found yet
.
TIGIT: CD28 chimeric receptor TIGIT (Vstm3) is an immunoglobulin superfamily, discovered in 2009
.
TIGHT belongs to the poliovirus receptor family, which also includes: PVR(CD155), CD96, CD112(PVRL2), CD112R(PVRIG), CD226(DNAM-1)
.
TIGIT, CD96, PVRIG and CD226 are expressed on T cells and NK cells, and CD155 and CD112 are expressed on DC cells and tumor cells
.
TIGIT is expressed in activated T cells and is a molecule that maintains the immune balance in the body
.
TIGIT is expressed in Treg and secretes IL-10 and Fgl2 to suppress immunity
.
In the tumor microenvironment, TIGIT is expressed in CD8 + TILS and a variety of tumor cells, as well as Treg
.
The research of TIGIT-28 is currently mainly in the laboratory stage and has not yet entered clinical practice
.
Some researchers compared TIGIT/28TMTIGIT (the transmembrane area of the extracellular segment of TIGIT plus the intracellular segment of CD28) and TIGIT/28TM28 (the extracellular segment of TIGIT plus the intracellular segment of the transmembrane area of CD28), and the former has better activity than the latter
.
CD200R: CD28 chimeric receptor CD200 is expressed on various types of tumor cells and binds to T cell CD200R to inhibit T cell activation
.
Oda et al.
compared chimera molecules with different transmembrane domains and handle region lengths, and the experimental results showed that CD200R-9aas-CD28cys is the best for T cell proliferation
.
This structure contains the extracellular domain of CD200 (AA1-229), which is fused to the AA142-218 region of CD28
.
CD28 membrane proximal cysteine (AA142) is integrated into this optimal receptor to promote disulfide bond-mediated homodimerization and enhance natural CD28 signal transduction
.
In the mouse leukemia model, the modified T cells showed a higher survival rate and the activity of controlling tumor growth
.
In phase 2 clinical trials (NCT01640301, NCT02408016), human CD200R-9aas-CD28cys receptor can also effectively enhance the proliferation of CD8+ T cells and is activated by human tumor cells expressing CD200 (Reference 5)
.
Cytokine chimeric receptors Several inhibitory cytokines and receptors inhibit the anti-tumor T cell response
.
The tumor microenvironment usually has a high level of IL-4, which promotes immune suppression by inducing the polarization of Th2 cells and M2 macrophages, while inhibiting the polarization of Th1 cells and the production of pro-inflammatory cytokines by antigen-presenting cells (APCs)
.
IL-4αβ switch receptor In order to inhibit the effects of IL-4, Wilkie et al.
developed a chimeric IL-4 receptor called 4αβ, which incorporates the extracellular domain of IL-4Rα (AA1-233).
To the transmembrane and extracellular domain of IL-2Rβ (AA241-551)
.
Transfer 4αβ and CAR into CTLL-2T cell line through SFG retroviral vector, and adding IL-4 can promote the proliferation of CTLL-2T cell line, and increase the secretion of IL-2 and IFN-γ, showing that the inhibitory signal is converted to Stimulus signal
.
IL-4/7 ICRMohammed et al.
produced a chimeric receptor called 4/7 inverted cytokine receptor (ICR), which contains the extracellular domain of IL-4Rα (AA1-233) And the transmembrane and intracellular domains of IL-7Rα (AA240-459)
.
When used alone, 4/7ICR cells can respond to IL-4 and promote T cell proliferation, but cannot induce anti-tumor activity
.
In xenograft tumor models in vitro and in humanized mice, the combination of 4/7 ICR and CAR can lead to antigen- and cytokine-dependent anti-tumor T cell responses
.
IL-4/21ICRWang et al.
developed a similar receptor 4/21ICR, which uses the IL-4Rα extradomain (AA1-233) and the transmembrane and intracellular domains of IL-21R (AA233-538)
.
In the presence of IL-4, CAR-T cells expressing IL-4/21 ICR differentiated into a Th17-like phenotype, and showed enhanced persistence and anti-tumor activity
.
The editor concludes that the poor inhibitory immune microenvironment of tumors is a key factor in the failure of CAR-T therapy to make significant progress in solid tumors
.
Based on this, scientists thought about converting inhibitory signals into stimulatory signals, resulting in ITS (inhibitory signal-to-stimulatory signal) chimeric receptor T cell therapy, which is different from the classic chimeric antigen receptor CAR-T therapy
.
Current research is mainly focused on immune checkpoints (PD-1, CTLA-4, etc.
) and inhibitory cytokines (IL-4, etc.
), most of which are still in the pre-clinical laboratory stage, PD-1: CD28 chimeric receptor The therapy has begun to enter the clinic and has made some progress
.
References 1.
Guo J, Kent A, Davila E.
Chimeric non-antigen receptors in T cell-based cancer therapy.
Journal for ImmunoTherapy of Cancer 2021;9:e002628.
doi:10.
1136/jitc-2021-0026282.
Hui Liu et al, CD19-Specific CAR-T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor is Effective in Patients with PD-L1 Positive B-Cell Lymphoma, Clin Cancer Res.
2021 Jan 15;27(2):473- 484.
3.
Lin S, Cheng L, Ye W, Li S, Zheng D, Qin L, Wu Q, Long Y, Lin S, Wang S, Huang G, Li P, Yao Y and Sun X (2021) Chimeric CTLA4-CD28 -CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86--Positive B Cell Malignancies.
Front.
Immunol.
12:642528.
4.
Hoogi S, Eisenberg V, Mayer S, et al.
A TIGIT-based chimeric costimulatory switch receptor improves T-cell anti -tumor function.
J Immunother Cancer 2019;7:2435.
Oda SK, Daman AW, Garcia NM, et al.
A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia.
Blood 2017;130:2410–96.
Wilkie S, Burbridge SE, Chiapero-Stanke L, et al.
Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4.
J Biol Chem.
2010;285(33):25538–25544.
doi:10.
1074/jbc.
M110.
12795178.
7.
Leen AM, Sukumaran S, Watanabe N, et al.
Reversal of tumor immune inhibition using a chimeric cytokine receptor.
Mol Ther.
2014;22(6):1211–1220.
doi:10.
1038/mt.
2014.
4779.
8.
Mohammed S, Sukumaran S, Bajgain P, et al.
Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer.
Mol Ther.
2017;25(1):249–258.
doi:10.
1016/j.
ymthe.
2016.
10.
01680.
9.
Wang Y, Jiang H, Luo H, et al.
An IL-4/21 inverted cytokine receptor improving CAR-T cell potency in immunosuppressive solid-tumor microenvironment.
Front Immunol.
2019;10:1691.
doi:10.
3389/fimmu.
2019.
016918110.
Babak Moghimi et al, Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma, Nat Commun.
2021 Jan 21;12(1):511.
