CAR-T immunotherapy and cancer therapy

Cell therapy is a kind of medicine aiming to cure disease or alleviate disease symptoms via direct infusion or transplantation of cells, which can be autologous or allogeneic. With several decades’ development and optimization, immuno-oncology cells (such as T cells, nature killer

Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are T cells genetically engineered to express CAR (Fig. 2A) [2,3], which can specifically recognize their target antigen via the scFv binding domain of CAR, resulting in T cell activation to specifically target and destroy tumor cells [3-5]. To date, four generations of CAR have been developed according to the structure of the endodomain (Fig. 2B) [3]. Due to little ability to generate enough interleukin-2 (IL-2), the 1st generation CAR-T cells (such as Ag-specific CD3ζ (MFEζ)-CAR-T cells, alpha-folate receptor (FR) -CAR-T cells, CE7R-CAR-T cells, scFv(G250)-CAR-T cells, GD2- CAR-T cells and CD10- CAR-T cells) benefitted substantially from the combination of cytokines [6], and were used for the treatment of different tumors [7-10]. However, most of the studies using the 1st generation CAR-T cells did not show very satisfactory results because of the inadequate proliferation, cytotoxicity, and insufficient secreted cytokines in vivo. To overcome these shortcomings, the 2nd generation CAR-T cells were designed by adding intracellular signaling domains from various co-stimulatory protein receptors to the cytoplasmic tail of the CARs, [11-13]. The 2nd generation CAR-T cells, such as scFvCD19-CD137-CD3-CAR-T cells, MOv19-BBζ-CAR-T cells and scFvCD19-CD28-CD3ζ-CAR-T cells displayed better curative effects on B cell malignancies [12,14]. On the basis of the 2nd generation CAR-T cells, the 3rd generation CAR-T cells were produced with the addition of multiple signaling domains, such as CD3ζ-CD28-OX40 or CD3ζ-CD28-41BB, to promote cytokine production and killing ability. The 3rd generation CAR-T cells, such as CD20-CD28-CD137-CD3ζ-CAR-T cells and HER2-CAR-T cells were applied for the treatment of lymphoma and colon cancer, but with no better outcomes than the 2nd generation CAR-T cells, and the reasons need to be further studied [15,16]. Based on the 2nd generation CAR-T cells, the 4th generation CAR-T cells were obtained with the addition of IL-12, and can mediate T cell redirected for universal cytokine-mediated killing (TRUCKs). TRUCK T cells show great outcomes in disease therapy by augmenting T-cell activation, and also activating and recruiting innate immune cells to destroy the antigen-negative cancer cells in the targeted lesion, and can also be used for the therapy of viral infections, metabolic disorders and auto-immune diseases [17]. Overall, these successive generations of CAR-T cells have yielded remarkable efficacy in several types of cancer or tumor therapy, and some of them have been translated into clinical trials with few side effects (Table 1) [18].

Figure 2 Structures of chimeric antigen receptor (CAR) [3]. (A) CAR structure: The CAR contains antigen recognition domain of thesingle-chain Fragment variant (scFv) derived from an antibody, transmembrane domain and an intracellular T cell activation domain of CD3ζ. (B) Evolution of CAR. ITAM: immunoreceptor tyrosine-based activation motifs. CM1: costimulatory molecule.
Table 1. Examples of CAR T-cell therapies in tumors [5]
AntigenDiseaseIn vitro, in vivo, in preclinical or in clinical trialsNCT/Reference
CD19haematologic malignanciesclinical trials[19-22]
CD20haematologic malignanciesclinical trials[23,24]
TRAIL receptor 1LymphomaIn vitro[25]
KappaLymphomaclinical trialsNCT00881920
CD22follicular lymphoma, non-Hodgkin’s lymphomaclinical trialsNCT02315612
HA-1 HLeukaemiaIn vitro[26]
NKG2DLeukaemiaclinical trialsNCT02203825
FAPB cell chronic lymphocytic leukaemiaclinical trialsNCT01722149
ROR1chronic lymphocytic leukaemiaclinical trialsNCT02194374
CD138multiple myelomaclinical trialsNCT01886976
NY-ESO-1multiple myelomaIn vitro[27]
Lewis Ymultiple myelomaclinical trialsNCT01716364
HER2OsteosarcomaIn vitro[28]
HER2Breast cancerIn vitro[29]
HER2SarcomaClinical trialNCT00902044
HER2Metastatic cancerClinical trialNCT00924287
HER2GlioblastomaClinical trialNCT01109095
HER2Solid tumorsClinical trialNCT01935843
CEAColorectal cancerIn vivo[30]
CEAColorectal cancerClinical trialNCT00673322
CEABreast cancerClinical trialNCT00673829
CEALiver metastasesClinical trialNCT01373047
CEAMetastatic cancersClinical trialNCT01723306
CSPG4Melanoma, breast carcinomaIn vivo[31]
EphA2GlioblastomaIn vivo[32]
FROvarian cancerIn vivo[33]
IL-11RαOsteosarcomaIn vivo[34]
IL-13Rα2GlioblastomaPreclinical trial[35]
IL-13Rα2Malignant gliomaClinical trialNCT02208362
IL-13RGliomaPreclinical trial[36]
CD171NeuroblastomaClinical trialNCT02311621
EGFRAdvanced EGFR-positive solid tumorsClinical trialNCT01869166
EGFRAdvanced gliomaClinical trialNCT02331693