| Years | CAR Target | Cancer/ Model | Small Molecule/Drug | Target | Statement | Ref. | |
| Reversible spatio-temporal control of CAR | |||||||
| 2021 | CD19 | B ALL and lymphoma | Thalidomide analogs | C2H2, CRBN | ON-Switch: drug-dependent activity of antitumor and thalidomide analogues prevented spilt CAR dissociation. OFF-switch: inflammatory cytokine production is limited to retaining antitumor and thalidomide analogue induced CAR proteasomal deterioration. | [66] | |
| 2020 | GD2 | FAP+ Mesothelioma | Shield-1 | LID domain-based CAR degradation | Induce drug-dependent CAR degradation and reduce CAR T cell activity temporarily. | [67] | |
| 2020 | CD19 | B ALL | ARV-771 or ARV-825 (retinol) | Bromodomain (BD of brd4) | Induce drug-dependent CAR degradation and reduce CAR T cell activity temporarily. | [68] | |
| 2020 | PSMA | prostate | A-1155463, A-1331852 (BH3 mimetic) | LD3/Bcl-xL-based CAR dimerization | STOP-CAR: inactivate CAR T cell dynamically and reversibly. | [69] | |
| 2020 | CD19 | B ALL | A1120 | hRBP4 and hRBP4 binders (RS3) | Drug-dependent regulation of CAR T cell activity. | [70] | |
| 2019 | CD22 | B ALL lymphoma | Asunaprevir | HCV NS3 protease | Switch-OFF CAR (SWIFF-CAR): proteolysis to constitutive CAR degron; dependent CAR degradation in Asunaprevir. | [71] | |
| 2019 | CD19 | B ALL | dasatinib | SRC kinases | Reversibly suppress CAR lymphocyte cytotoxicity, cytokine secretion and proliferation. | [72] | |
| 2019 | CD19 | B ALL lymphoma | dasatinib | SRC kinases | Reversibly suppress CAR lymphocyte cytotoxicity, cytokine secretion. and proliferation. | [73] | |
| 2018 | CD19 | Cd19= K562 | ABT-737 | Fab (AZ1) specific for Bcl-xL only in the attendance of ABT-737 | CAR T cell activation is drug -dependent. | [74] | |
| 2017 | PSCA, GD2, CD123 | Prostate, melanoma, AML | AP1903(rimiducid) | FKBP/FRB-based dimerization of MyD88/CD40(iMC) | Intensify CAR therapy proliferation and activity of anti-tumor. | [75] | |
| 2015 | CD19, MESO | CD19+ or Meso+ K562 | Rapalog, (gibberellic acid) | FKBP/FRB-(or GID1/GAI)-based CAR dimerization | ON-switch CAR: Timing, location and dosages are controlled by CAR therapy activity and mitigate noxiousness. | [76] | |
| Modulating CAR specificity | |||||||
| 2021 | CD33, EGFR | AML, GBM | Methotrexate | Conditional scFvs | Decrease of CAR T cell affinity and cytotoxicity, reversible in drug-induced. | [77] | |
| 2018 | HER-2, Axl, Meso | HER-2+, Axl+, Meso+ K562 | Soluble zipFv | Membrane-bound zipCAR | SUPRA-CAR: controls signaling, fine-tunes T cell activation, mitigates toxicity and allow multiple antigen sensing. | [78] | |
| 2016 | 5B9 epitope of La/SS-B | AML (others) | 5B9-tagged anti-CD33 and anti-CD123 antibodies | CD33, CD123 | Uni-CAR T (Universal): Redirect CAR in a time-and target-dependent manner; potent anti-AML activity. | [79] | |
| 2016 | FITC | B ALL and lymphoma | FITC-modified anti-CD19 and anti-CD22 antibodies | CD19, CD22 | Enable CAR-switch combinations; potent and dose-dependent antitumor activity. | [80] | |
| Combinatorial anti-cancer approaches | |||||||
| 2020 | CD19 | B ALL | >500 small molecules | Multiple | Primary; birinapant, AT-406, LCL-161 (SMAC mimetics /inhibitor of apoptotic antagonists); Secondary: bryostatin-1 (PKC activator), idasanutlin and nutlin-3 (MDM2 inhibitors): Enhance CAR T cells cytotoxicity. | [81] | |
| 2020 | CAIX | RCC (lung metastasis) | sunitinib | Multiple Kinases | Up-regulate CAIX in tumor cells; decrease MDSCs frequency. | [82] | |
| 2018 | CD19 | NHL | Suberoylanilide hydroxamic acid and LBH589; Celecoxib | Histone deacetylase; cyclo-oxygenase-2 | Enhance CAR T cells cytotoxicity. | [83] | |
| 2018 | FLT3 | AML | crenolanib | FLT3 kinase | Synergize anti-leukemia effect. | [84] | |
| 2017 | CD19 | B ALL | Akt inhibitor VIII | Akt | Akt signaling inhibition during CAR T cell expansion improve antitumor efficacy. | [85] | |
| 2013 | CD19 | B ALL | ABT-737; ABT-263 (navitoclax) | Bcl-2 family members | Restore intrinsic apoptosis in tumor cells; Enhance CAR T cells efficacy. | [86] | |
| 2013 | HER-2 | HER-2+ PD-1+ tumor cells | Anti-PD-1 mAb | PD-1 | Decrease MDSCs frequency; Enhance CAR T cell function. | [87] | |
| 2013 | CD19 | CLL | ibrutinib | Bruton’s tyrosine kinases | Tumor clearance and mice survival and improved CAR T cells engraftment. | [49] | |
| Mitigating the adverse effects | |||||||
| 2019 | CD19 | B ALL | lenzilumab | GM-CSF | Inhibit CRS and neurotoxicity. | [88] | |
| 2018 | CD19 | B lymphoma | anti-IL-6 and anti-IFN-γ mAb | IL-6 and IFN-γ | Reduce toxicity | [89] | |
| 2018 | CD19, CD44v6 | B ALL | anakinra, tocilzumab | IL-1 antagonist-receptor, IL-6 | Inhibit CRS and neurotoxicity; extend leukemia-free survival. | [90] | |
| 2018 | CD19 | B ALL | anakinra; L-NIL and 1400W | IL-1 antagonist-receptor, iNOs inhibitors | Suppress CRS-related mortality by inhibiting macrophage-derived products (Nos, IL-1 and IL-6); | [91] | |
| 2018 | CD19 | B lymphoma | metyrosine | catecholamines | Keep mice safe from CRS lethal complication | [92] | |
| 2016 | CD19 | B ALL | Etanercept, infliximab | TNF-α | To reduce toxicity | [93] | |
| Elimination of CAR T Cell | |||||||
| 2018 | CD19 | B ALL and lymphoma | AP20187, rapamycin | FKBP/FRB Inducible caspase 9 (rapaCasp9) | The in vivo process eliminates. | [94] | |
| 2017 | CD19 | B lymphoma | AP1903 (rimiducid) | FKBP/FRB Inducible caspase 9 (iCasp9) | CAR T cell eradication is extremely dose- dependent manner. | [95] | |
| 2014 | GD2 | N/A | rituximab | CD20 epitope fused to CD8 stalk (RQR8, also contain tCD34) | Enable CAR T cell selection, cell tracking (tCD34), and deletion (CD20). | [96] | |