Background
CAR-T profile
History and evolution
CAR generations | Signal domain | Target antigen | Associated diseases | Profile | References |
---|---|---|---|---|---|
1st | |||||
CD3ζ | TAG72 | Metastatic colorectal cancer | Limited persistence | [84] | |
CD3ζ | FRα | Ovarian cancer | Limited persistence | [26] | |
CD3ζ | L1-CAM | Metastatic neuroblastoma | Limited persistence | [85] | |
2nd | |||||
CD3ζ + CD28/CD137 (41BB) | CD19 | B cell lymphomas | Enhanced expansion, persistence and anti-tumor effect | ||
CD3ζ + 41BB(CD137) | IL13Rα2 | GBM | Improved anti-tumor activity and T cell persistence | [22] | |
CD3ζ + 41BB (CD137) | FRα | Ovarian cancer | Augmented cytokine secretion and proliferation | [88] | |
3rd | |||||
CD3ζ + CD28 + 41BB(CD137) | CD19 | ALL | Superior activation and proliferation capacity | [89] | |
CD3ζ + CD28 + 41BB(CD137) | PMSA | – | Promoted cytokine release, T-cell survival and tumor elimination | [90] | |
CD3ζ + CD28 + CD137 (41BB) | Mesothelin | Mesothelioma | Prolonged persistence | [30] | |
CD3ζ + CD28 + 41BB(CD137) | CD22 | ALL | Inferior antileukemic activity | [32] | |
4th | |||||
CD3ζ + iIL-12+ co-stimulator | CEA | CEA+ tumors | Improved antitumor efficacy | [35] |
Structure
Preparation
Therapeutic effect of CAR-T in different systems
Tumors | scFv | Single domain | Dose (cells /kg or cells/ m2) | Clinical trials (phage and NCT number) (www.clinicaltrials.gov/) | Number of treated patients | Responses | Persistence | References |
---|---|---|---|---|---|---|---|---|
ALL | CD19 | CD28 + CD3ζ | 1.5 × 106 to 3 × 106 | Phase I (NCT01044069) | 5 | 5 CR | Uncertaina | [87] |
ALL | CD19 | CD137+ CD3ζ | 1.4 × 106 to 1.2 × 107 | Phase I (NCT01626495) | 2 | 2 CR | One persisted 11 months, the other relapsed | [45] |
ALL | CD19 | 41BB + CD3ζ | 0.76 × 106 to 20.6 × 106 | Phase I/ ΙΙ (NCT01626495) ( NCT01029366) | 30 | 27 CR | 2 to 3 months | [48] |
ALL | CD19 | CD28 + CD3ζ | 3 × 106 | Phase I (NCT01044069) | 16 | 14 CR | 2 to 3 months | [52] |
ALL | CD19 | CD28 + CD3ζ | 1 × 106 (maximum) | Phase I (NCT01593696) | 21 | 12 CR | Un stated | [13] |
CLL | CD19 | CD137+ CD3ζ | 1.5 × 105 | Phase I (NCT01029366) | 3 | 3CR | 10 months | [46] |
CLL | CD19 | CD28 + CD3ζ | 0.2–1.1 × 107 | Phase I (NCT00466531) | 8 | 1 PR | uncertain | [91] |
CLL | CD19 | CD28 + CD3ζ | 1 × 106, 1.5 × 106, 4 × 106 | Phase I (NCT01087294). | 10 | 3 CR | < 1 month | [92] |
CLL | CD19 | 41BB + CD3ζ | 0.14 × 108 to 11 × 108 | Phase I (NCT01029366) | 14 | 4 CR, 4 PR | 14 to 49 months | [49] |
CLL | CD19 | 41BB + CD3ζ | 1.6 × 107; 1.0 × 107; 1.46 × 105 | Phase I (NCT01029366) | 3 | 2 CR, 1 PR | > 6 months | [93] |
CLL/NHL/MM | κ light chain | CD28 + CD3ζ | 2 × 107, 1 × 108, 2 × 108 | NCT00881920 | 16 (9 CLL/NHL, 7 MM) | 2 CR, 1 PR | 6 weeks | [94] |
CLL | CD19 | CD28 + 41BB+ CD3ζ | 2 × 105, 2 × 106, or 2 × 107 | unstated | 24 | 4 CR, 10 PR | 6 months | [95] |
MM | CD19 | CD137+ CD3ζ | 1 × 107 to 5 × 107 | Phase I (NCT02135406) | 10 | Uncertain | – | [54] |
Lymphomas | CD19 | 41BB+ CD3ζ | 3.08 × 106 to 8.87 × 106 | NCT02030834 | 28 | 16 CR | 29.3 months | [47] |
NSCLC | EGFR | CD137+ CD3ζ | 0.45 to 1.09 × 107 | Phase I (NCT01869166) | 11 | 2 PR, 5 SD | 2 to 8 months | [20] |
CCA | EGFR | CD137+ CD3ζ | 2.2/2.1 × 106, 1.22 × 106 | Phase I (NCT01869166) (NCT02541370) | 1 | 1 PR | 13 months | [63] |
CRC | CEA | CD28/CD137+ CD3ζ, CD28+ D137+ CD3ζ | 1 × 105 to 1 × 108 | Phase I (NCT02349724) | 10 | 7 SD | – | [33] |
SVC | MUC1 | CD28+ 4-1BB+ CD3ζ | 5 × 105 | Phase I/II (NCT02587689) | 1 | Tumor necrosis | Unstated | [68] |
GBM | GD2 | unstated | 2 × 107, 5 × 107, 1× 108 | Phase I (NCT00085930) | 19 | 3CR | > 6 weeks | [69] |
GBM | EGFRvIII | 41BB + CD3ζ | 1 × 107 | Phase I (NCT02209376) | 10 | 1SD | – | [70] |
GBM | HER2 | CD28+ CD3ζ | 1 × 106 to 1 × 108 | Phase I (NCT01109095) | 17 | 1 PR, | > 9 months | [71] |
7 SD | ||||||||
GBM | IL13Ra2 | 41BB + CD3ζ | 2 × 106, 10 × 106 | Phase I (NCT02208362) | 1 | Tumor necrosis | 7.5 months | [72] |
Sarcoma | HER2 | CD28+ CD3ζ | 1 × 104 to 1 × 108 | Phase I/II (NCT00902044) | 19 | 4 SD | – | [74] |