Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents
Abstract
:Simple Summary
Abstract
1. Introduction
2. CAR Construct
2.1. Basic Design of CAR
2.2. A Novel Design of CAR
2.3. Transmembrane and Hinge Domains of CAR
2.4. CAR Contructs Designed to Exhibit Reduced T Cell Activiation Lead to the Superior Antitumor Activity
2.5. Antigen-Binding Domains of CAR
3. Genetic Engineering to Express or Delete Specific Proteins
3.1. Expression of Specific Proteins
3.2. Depletion of Specific Proteins
3.3. Inhibition of TGF-β Signaling
3.4. Genome Editing Technology in CAR T Cell
3.5. Inhibition of PD-1 Signaling
3.6. Chemokine Receptors
3.7. Interleukins
3.8. Artificial Cytokine Receptors
4. Synergistic Effects of CAR T Cell Therapy with Compounds
4.1. Compounds Enhancing CAR T Cell Activity
4.2. Usage of Compounds for T Cell Ex Vivo Culture
4.3. Anti-Angiogenic Agents for CAR T Cells
4.4. Safety System to Block the Side Effects of CAR T Cells
4.5. Compounds Inducing Antigen Expression
4.6. Usage of Vaccines to Enhance CAR T Cell Activity
4.7. Radiotherapy Combined with CAR T Cell Therapy
4.8. Compounds Used in Clinical Trials of CAR T Cells
5. Manufacturing Process/Ex Vivo Culture Method
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Target Proteins | Method | Effect | Reference |
---|---|---|---|
TERT | Expression | Escaping cell senescence; Prolonged in vivo persistence | [95] |
Heparanase | Expression | Degrading heparin sulfate proteoglycan; Improved tumor infiltration | [96,97,98] |
JUN | Expression | Improved IL-2 production; Escaping T cell exhaustion | [99] |
PD1 or PDL1 scFv | Expression | Suppressing the immune inhibitory signaling | [100,101,102] |
sPD1 | Expression | [103] | |
Chemokine receptors (CXCR1, CXCR2, CCR2, CCR4, CCR2b) | Expression | T cell’s trafficking; Enhanced trafficking to tumor lesion | [104,105,106,107,108,109,110] |
Interleukins (IL12, IL18, IL15, IL21, IL23, IL36γ, IL7) | Expression | Enhanced tumor infiltration of CAR T cell; Modulate tumor microenvironment to increase M1 macrophage; Generate T-memory stem cell | [111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130] |
NR4A | shRNA | Inhibition of PD1, TIM3 expression | [131] |
Tet2 | shRNA | Driving T cells into central memory phenotype | [132] |
PTPN2/22 | shRNA | Upregulation of TCR signaling by Lck phosphorylation | [133,134,135,136] |
TGFβ signaling | SD-208 (kinase inhibitor) | Increasing CAR T cell viability & suppressing PD-1 expression | [137] |
KO of TGFβ receptor | Suppressed Treg conversion and CAR T cell exhaustion | [138] | |
Expressing of dominant negative (DN) TGFβ receptor II | Enhanced cytokine secretion & Increased CAR T cell proliferation | [139] | |
Cholesterol esterification enzyme | shRNA | Elevated cholesterol level triggers the proliferation and cytotoxic activity of T cell | [140] |
inhibitor | [141] | ||
DGK | Knockout | Reinvigorate the function of hypofunctional tumor-infiltrating immune cells | [142] |
PD1 | Knockout | Suppressed the immune inhibitory signaling | [143] |
PD1 decoy receptor | [144,145,146,147,148,149,150,151] | ||
A2aR | shRNA | Increased CAR T cell efficacy | [152] |
Compounds | Function | Effect | Reference |
---|---|---|---|
Afatinib | Tyrosine kinase inhibitor | Increase NK cell infiltration into tumor | [192] |
Lenalidomide | Immunomodulatory drug | Increase cytotoxicity, cytokine production of CAR T cell | [193] |
Bortezomib | Proteasome inhibitor | Augment anti-tumor effect of CAR T cell | [195] |
AMG102 | HGF receptor neutralizing antibody | Increase CAR T cell trafficking into tumor | [196] |
pI:pC (polyinosinic-polycytidylic acid) | Immunostimulation by interacting with toll-like receptor 3 | Diminish suppressive activity and cell number of MDSC | [203] |
ATRA (All-Trans Retinoic Acid) | Agonist for the retinoic acid receptors | Eradicate monocytic MDSC | [204] |
Gemtuzumab ozogamicin | CD33 antibody conjugated with calicheamicins | Remove MDSC | [205] |
SCH58261 | A2aR antagonist | Elevate the proliferation rate and cytokine production of CAR T cell | [207] |
SB216763 | GSK3β inhibitor | Downregulating PD1 and FasL expression | [211] |
MK2206 | Akt inhibitor | Increase CAR expression; Induced CD62L expressing central memory phenotype | [212] |
AKTi | [213] | ||
JQ1 | Bromodomain inhibitor | Maintain T cells with central memory and stem cell like phenotype | [214] |
IPI-549 | PI3Kγ inhibitor | Exhibit potent antitumor activity | [215] |
CAL-101 | PI3Kδ inhibitor | ||
Combretastatin A-4 phosphate (CA-4) | Vascular disrupting agent | Anti-angiogeneic agent; Improve the infiltration of CAR T cell into solid tumor | [216] |
Bevacizumab | VEGF-a antibody | [217] | |
Ibrutinib | BTK/ITK inhibitor | Enhanced one-year PFS; Reduced the serum level of CRS-associated cytokines | [218,219] |
Dasatinib | ABL inhibitor | Complete remission in CML patient treated with CD19 CAR T cell | [220] |
Decitabine | DNA methyltransferase inhibitor | Complete remission in B cell lymphoma patients treated with CD19 CAR T cell | [221] |
Compounds Plus Genes | Mechanism | Effect | Reference |
---|---|---|---|
TO-207 | mRNA 3′-end processing antagonist | Block cytokine production in monocyte | [243] |
Dasatinib | Multikinase targeted inhibitor | Block CRS by suppressing lymphocyte-specific protein tyrosine kinase (lck) | [244,245] |
Rimiducid plus iCasp9 | Dimer of mutant FKBP12 (F37V) ligand | Induce dimerization of caspase-9 leading to apoptosis | [48,231,232,233,234,235,236,237] |
ARV-771 plus bromodomain containing CAR | PROTAC compound against bromodomain | Induce degradation of CAR protein leading to suppress the activity of CAR T cell | [238] |
Asunaprevir plus CAR containing protease and degron | Protease inhibitor | Induce degradation of CAR protein leading to suppress the activity of CAR T cell | [239] |
4-ipomeanol plus optimized CYP4B1 | prodrug | Mutant CYP4B1 converts 4-ipomeanol to cytotoxic alkylating agent. | [240] |
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Park, C.H. Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents. Cancers 2021, 13, 3236. https://doi.org/10.3390/cancers13133236
Park CH. Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents. Cancers. 2021; 13(13):3236. https://doi.org/10.3390/cancers13133236
Chicago/Turabian StylePark, Chi Hoon. 2021. "Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents" Cancers 13, no. 13: 3236. https://doi.org/10.3390/cancers13133236
APA StylePark, C. H. (2021). Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents. Cancers, 13(13), 3236. https://doi.org/10.3390/cancers13133236