Introduction
Development, classification, and distribution of NK cells
The activation and inhibition of NK cells
Inhibitory and activating signals
Receptors | CD | Structure | Ligand | Signal molecule | Chromosome |
---|---|---|---|---|---|
KIR2DL1 | CD158b | Ig monomer | HLA-C, N77/N80 | ITIM | 19q13.4 [97] |
KIR2DL2 | CD158b1 | Ig monomer | HLA-C, S77/N80 | ITIM | 19q13.4 [97] |
KIR2DL3 | CD158b2 | Ig monomer | HLA-C, S77/N80 | ITIM | 19q13.4 [97] |
KIR3DL1 | CD158e1 | Ig monomer | HLA-Bw4 | ITIM | 19q13.4 [105] |
KIR3DL2 | CD158k | Ig monomer | HLA-A3, HLA-A11 | ITIM | 19q13.4 [106] |
KIR2DL5A/B | CD158f | Ig monomer | Unknown | ITIM | 19q13.4 [107] |
LAIR-1 | CD305 | Ig monomer | Collagen | ITIM | 19q13.4 [107] |
LILRB1(ILT2) | CD85j | Ig monomer | HLA-I | ITIM | 19q13.4 [108] |
SIGLEC7(p75) | CDw328 | Ig monomer | Α-2,8 disialic acid | ITIM | 19q13.3 [109] |
CEACAM1 | CD66a | Ig monomer | CD66 | ITIM | 19q13.2 [107] |
CD94-NKG2A(KLRD1-KLRC1) | CD159a | C lectin heterodimer | HLA-E | ITIM | 12p13 [110] |
KLRG1 | C lectin heterodimer | Cadherins | ITIM | 12p12-p13 [107] | |
NKR-P1A(KLRB1) | CD161 | C lectin heterodimer | LLT-1 | ITIM | 12p13 [107] |
2B4 | CD224 | Ig monomer | CD48 | ITIM | 1q23.1 [107] |
Receptors | CD | Structure | Ligand | Signal molecule | Chromosome |
---|---|---|---|---|---|
2B4 | CD224 | Ig monomer | CD48 | ITSM, SAP | 1q23.1 [107] |
KIR2DS1 | CD158h | Ig monomer | HLA-C, N77/N80 | DAP12 | 19q13.4 [97] |
KIR2DS2 | CD158j | Ig monomer | Unknown | DAP12 | 19q13.4 [111] |
KIR2DS4 | CD158i | Ig monomer | HLA-Cw4 | DAP12 | 19q13.4 [66] |
KIR3DS1 | CD158e2 | Ig monomer | Unknown | DAP12 | 19q13.4 [112] |
KIR2DL4 | CD158d | Ig monomer | HLA-G | FcεRIγ | 19q13.4 [113] |
NKp46(NCR1) | CD335 | Ig monomer | HV | FcεRIγ, CD3ζ | 19q13.4 [78] |
NKp44(NCR2) | CD336 | Ig monomer | HV | DAP12 | 6p21.1 [100] |
NKp30(NCR3) | CD337 | Ig monomer | Pp65, BAT-3, B7-H6 | FcεRIγ, CD3ζ | 6p21.3 [100] |
FCGR3(FcγRIII) | CD16 | Ig monomer | IgG | FcεRIγ, CD3ζ | 1q23 [114] |
DNAM-1 | CD226 | Ig monomer | CD112, CD155 | Protein kinase C | 18q22.3 [115] |
SLAMF7 | CD319 | Ig monomer | CRACC | ITSM, EAT2 | 1q23.1–4 [116] |
SLAMF6 | No | Ig monomer | NBT-A | ITSM | 1q23.2 [117] |
TACTILE | CD96 | Ig monomer | CD112, CD155 | Unknown | 3q13-q12.2 [118] |
CD27 | CD27 | Ig monomer | CD70 | TRAF2, TRAF5, SIVA | 12p13 [119] |
CD94-NKG2C(KLRD1-KLRC2) | CD159c | C lectin heterodimer | HLA-E | DAP12 | 12p13 [120] |
CD94-NKG2E | No | C lectin heterodimer | HLA-E | DAP12 | 12p13 [120] |
NKG2D(KLRK1) | CD314 | C lectin heterodimer | ULBP1-4, MICA/B | DAP10 | 12p13 [87] |
NKp80(KLRF1) | No | C lectin heterodimer | AICL | Unknown | 12p13.2-p12.3 [79] |
Regulatory cytokines that increase NK cells in the TME
NK cell-mediated anti-tumor mechanisms
Direct cancer killing
Indirect cancer killing
NK cell-based therapeutic strategies
Cytokines
Allogeneic and autologous NK cell treatment
Cancer type | Source | Enrichment of NK cells | Lymphodepletion | Patient (N) | Clinical response |
---|---|---|---|---|---|
AML, CML, MDS | Haploidentical (HSTC donor) | CD3−CD56+ selection | None | 5 | CR in 4 [141] patients |
AML | Haploidentical | CD3 depleted PBMCs, IL-2 stimulation | Flu/Cy | 19 | CR in 5 patients [142] |
AML | Haploidentical | CD3 depleted PBMCs, IL-2 stimulation (n = 32) CD3 depleted PBMCs, CD56 selection, IL-2 stimulation (n = 10) | Flu/Cy | 42 | CR in 9 patients [125] |
AML | Haploidentical | CD3 depleted PBMCs (with or without CD56 selection), or CD3 and CD19 depleted PBMCs, IL-2 stimulation | 15 | CR in 8 patients [125] | |
AML | Haploidentical | CD3 and CD19 depleted PBMCs, IL-15 stimulation | Flu/Cy | 40 | CR in 7 patients [143] |
AML | Umbilical cord blood | Differentiation and expansion from CD34+ cells | Flu/Cy | 10 | CR in 10 patients[144] |
AML, CML | HSCT donor | CD3 depletion, co-culture with K562-mbIL-21 | HSCT conditioning | 13 | CR in 7 of 8patients with AML and in all 5patients with CML [145] |
MM | Autologous or haploidentical | Co-culture with K562-mbIL-15-4-1BBL, CD3 depletion | Bortezomib alone or with Flu/Cy and dexamethasone | 7 | Two patients were treatment-free for 6 months [146] |
B-NHL | Haploidentical | CD3and CD19depleted PBMCs, IL-2 stimulation, pretreatment with rituximab | Flu/Cy, methylprednisolone | 14 | CR in 2 patients; PR in 2 patients [147] |
Neuroblastoma | Haploidentical | CD3−CD56+selection, IL-2 stimulation, anti-GD2 after NK cell infusion | Cy, vincristine, and topotecan | 35 | CR in 5patients; PR in 5patients [148] |
RCC | Haploidentical | CD3depleted PBMCs, IL-2 stimulation | Flu | 7 | No[142] |
Melanoma, RCC | Haploidentical | CD3-depleted PBMCs, IL-2 stimulation | Cy and methylprednisolone | 16 | SD in 6patients[142] |
Ovarian cancer, breast cancer | Haploidentical | CD3-depleted PBMCs | Flu/Cy, TBI (2 Gy) | 20 | PR in 4patients; SD in 12patients [149] |
CAR-NK cell therapy
Background
Study overview
NK cell sources
Source | Advantages | disadvantages |
---|---|---|
PB | Mature phenotype Highly functional and cytotoxic | Only 5%–10% of PB lymphocytes are NK cells Heterogenous product Not readily available, need donors |
CB | Readily available from global CB banks.15%–30% of CB lymphocytes are NK cells. Transcriptomic profile supports high proliferative potential | Numerically few and therefore requires ex vivo expansion Heterogeneous product |
iPSC | High proliferative capacity Homogeneous product | Immature phenotype Low ADCC due to low CD16 expression Long culture condition |
NK-92 cell line | High proliferative capacity Easy to manipulate and engineer Homogeneous product Reduced sensitivity to freeze/thaw cycles | Derived from a patient with NK lymphoma Need for irradiation Limited in vivo persistence following irradiation Low ADCC due to low or absent CD16 expression |
Clinical efficacy of CAR-NK in cancers
AML
Lymphoma
MM
Solid tumors
Cancer type | ClinicalTrials.gov Identifier | Initial time | Phase | N | Primary study endpoint |
---|---|---|---|---|---|
R/R Non-Hodgkin Lymphoma | NCT04639739 CD19 | December 17, 2020 | Phase I | 9 | Incidence of dose limiting toxicity Incidence and severity of AEs and SAEs |
Relapsed and Refractory B Cell Lymphoma | NCT03692767 CD22 | March 2019 | Phase I | 9 | Occurrence of treatment related adverse events as assessed by CTCAE v4.0 |
Relapsed and Refractory B Cell Lymphoma | NCT03690310 CD19 | March 2019 | Phase I | 9 | Occurrence of treatment related adverse events as assessed by CTCAE v4.0 |
Epithelial Ovarian Cancer | NCT03692637 Mesothelin | March 2019 | Phase I | 30 | Occurrence of treatment related adverse events as assessed by CTCAE v4.0 |
metastatic Solid Tumours | NCT03415100 NKG2D-ligand | January 2, 2018 | Phase I | 30 | Number of Adverse Events |
Castration-Resistant Prostate Cancer | NCT03692663 PSMA | December 2018 | Phase I | 9 | Occurrence of treatment related adverse events as assessed by CTCAE v4.0 |
Solid Tumors | NCT03940820 ROBO1 | May 2019 | Phase I/II | 20 | Occurrence of treatment related adverse events as assessed by CTCAE v4.03 |
Relapse/Refractory MM | NCT03940833 BCMA | May 2019 | Phase I/II | 20 | Occurrence of treatment related adverse events as assessed by CTCAE v4.03 |
Recurrent/Metastatic Gastric or Head and Neck Cancer | NCT04847466 Irradiated PD-L1 | April 22, 2021 | Phase II | 55 | ORR |
Relapsed and Refractory B Cell Lymphoma | NCT03824964 CD19/CD22 | February 1, 2019 | Phase I | 10 | Occurrence of treatment related adverse events as assessed by CTCAE v4.0 |
B Lymphoid Malignancies | NCT04796675 CD19 | April 10, 2021 | Phase I | 27 | Incidence of Treatment-related Adverse Events |
Relapsed/Refractory CD33 + AML | NCT02944162 CD33 | October 2016 | Phase I/II | 10 | Adverse events attributed to the administration of the anti-CD33 CAR-NK cells |
CD19 Positive Leukemia and Lymphoma | NCT02892695 CD19 | September 2016 | Phase I | 10 | Adverse events attributed to the administration of the anti-CD19 CAR-NK cells |
Pancreatic Cancer | NCT03941457 ROBO1 | May 2019 | Phase I | 9 | Occurrence of treatment related adverse events as assessed by CTCAE v4.03 |
CD19 + Relapsed/Refractory Hematological Malignancies | NCT04796688 CD19 | March 10, 2021 | Phase I | 27 | Incidence of Treatment-related Adverse Events |
Relapsed/Refractory B-Lymphoid Malignancies | NCT03056339 CD19 | June 21, 2017 | Phase I/II | 36 | Toxicity and efficacy |