Table 2.

Genetic engineering strategies and combinational therapies potentiating CAR T-cell efficacy

(A) Genetic engineering strategies potentiating CAR T cells
TransgeneEffectsAntigen targetedTumor targetedReferences
Improve CAR T-cell infiltration/migrationCCR2Promotes CAR T-cell trafficking to the tumor following systemic administrationMSLNMesothelioma(54, 80)
CCR4Promotes CAR T-cell trafficking to the tumor following systemic administrationCD30Lymphoma(92)
HeparanaseDegrades the extracellular matrix, thereby improving CAR T-cell tumor infiltration and efficacyCSPG4Melanoma(93)
Improve CAR T-cell effector functionActive AKTThe constitutive AKT expression improves CAR T-cell survival, proliferation, cytokine secretion and renders them resistant to Treg suppressionGD2Neuroblastoma(82)
IL12Increases effector cytokine secretion, renders CAR T cells resistant to Treg-mediated inhibition, and induces host innate immune responseCD19Leukemia(94–97)
VEGFRMelanoma, sarcoma, and colon cancer stroma
IL15Improves T-cell expansion and reduces PD-1 expressionCD19Leukemia(98, 99)
IL7 or IL7RIncreases proliferation, survival, and effector function of CAR T cells even in the presence of TregsCD19Leukemia(99, 100)
IL21Increases CAR T-cell proliferation and cytotoxic efficacyCD19Leukemia(99, 101)
CD80 or 4-1BBLTrans-/autocostimulation between CAR T cells enhancing effector functionsPSMAProstate(102)
CD40LEnhances tumor cell immunogenicity, stimulates moDC, and increases CAR T-cell cytotoxic efficacyCD19Leukemia(103)
4αβ chimeric cytokine receptor4αβ generated by the fusion of IL4R ectodomain and IL2R and IL15R subunit enhances CAR T-cell long-term proliferation and cytotoxicityMUC1Breast(104)
ERBBHead and neck
Counteract immunosuppressionshRNA CTLA4Decreased CTLA4 expression enhances CAR T-cell proliferation and antitumor activityCD19Leukemia(105)
Improve specificity and safetyiCAR “safety switch”iCAR with PD-1 or CTLA-4 inhibitory intracellular domain linked to secondary antigen constrains CAR T-cell specificity to cancer cells expressing the primary antigenPSMAProstate(106)
(B) Preclinical investigation of combinational therapies potentiating CAR T-cell efficacy
AgentsEffectsAntigen targetedTumor targetedReferences
PreconditioningRadiotherapyTotal body irradiation (TBI)–induced lymphodepletion in the host promotes CAR T-cell efficacyEGFRvIIIGlioblastoma(107)
FlutamideFlutamide-induced androgen ablation acts in additive with CAR T cells in vitroMUC1Prostate(108)
ValproateSodium valproate–induced upregulation of tumor cell-surface NKG2DL expression enhances the immune recognition of CAR T cells in vitroNKG2DLOvarian(109)
Monoclonal antibodiesPD-L1 or PD-1 immune checkpoint blockadeBlocking the PD-1 immunosuppressive signaling enhances CAR T-cell proliferation, cytotoxicity, and cytokine secretionCEALiver metastases from colon cancer(48, 65, 110)
Bispecific antibodies EGFR/cMET or EGFR/EPCAMBispecific antibodies link EGFR-transduced CAR T cells to antigen-expressing tumor cells enhancing CAR T-cell recruitment/retention and cytotoxicityCEAColon(111)
Anti GM-CSF or Gr-1Reduction of myeloid-derived suppressor cell (MDSC) populationCEALiver metastases from colon cancer(65)
Small specific inhibitory drugABT-737Improves CAR T-cell killing by restoring apoptosis pathway in tumor cellsCD19Leukemia(112)
RapamycinInhibition of mTOR kinase decreases the expression of antiapoptotic molecules and others (VEGF, PD-L1, IL10) leading to a superior antitumor effect of CAR T cells engineered with mTOR resistanceCD19Leukemia(113)
BRAFi/MEKiInhibition of MAPK pathway blocks tumor cell growth and enhances apoptotic killing by CAR T cells in vitroGD2Melanoma(114)
Oncolytic virusAdenovirus vector expressing Rantes and IL15Adenovirus vector–mediated Rantes and IL15 expression in the tumor enhances CAR T-cell infiltration and persistenceGD2Neuroblastoma(115)
Whole-cell vaccineIrradiated K562 cells expressing CD40L and OX40LVaccination boosts antitumor efficacy of CAR T cellsGD2Lung(116)

Abbreviations: iCAR, inhibitory CAR; moDC, monocyte-derived dendritic cells.