Introduction
The structure and function of CLL-1
Expression in normal cells and AML
Diagnostic value and follow-up for minimal residual disease
Antibody-based therapy
Preclinical studies
Study | Antibody type | In vitro efficacy | Animal model | In vivo efficacy | Adverse effect |
---|---|---|---|---|---|
Zheng 2019 [41] | Anti-CLL-1-PBD | Highly active against AML cell line and primary AML cells | Mice | Significant decrease in leukemia burden | No weight loss and signs of moribundity |
Cynomolgus monkeys | N/A | Well toleration; welling at injection site; remarkable decrease of granulocyte and monocyte, minimal decrease of RBC; no effect on PLT and lymphocytes | |||
Jiang 2018 [43] | Anti-CLL-1-IQB | Effective to AML cell line and primary AML cell; inhibit LSC colony formation | Mice | Significant decrease in leukemia burden | No effect on engraftment or differentiation of CD34+ cells |
Zhao 2010 [19] | Anti-CLL-1 antibody | Effective to AML cell line and primary AML cells | Mice | Delayed tumor growth | N/A |
Wiersma 2015 [44] | scFvCLL-1:TRAIL | Upregulating TRAIL on granulocytes, improving anti-tumor activity of granulocyte; enhancing ADCC. | N/A | N/A | N/A |
Leong 2017 [1] | Anti-CLL-1/anti–CD3 bispecific antibody | Highly active against CLL-1+ AML cell lines and clinical AML samples, especially for CD3H. | Cynomolgus monkeys | N/A | Vascular shock with CLL-1/CD3H; well toleration with CLL-1/CD3L. Evident decrease of monocyte and granulocyte, early decrease of lymphocyte. |
Lu 2014 [46] | Anti-CLL-1/anti–CD3 bispecific antibody | High cytotoxicity to AML cell lines, modest cytotoxicity to primary AML. | Mice | Elimination of the tumor | No effect on body weight and other status |
Loo 2015 [47] | Anti-CLL-1/anti–CD3 bispecific antibody | Efficiently activating T cells, potent anti-leukemia against primary AML cells | N/A | N/A | N/A |
Clinical trial
Chimeric antigen receptor T cell therapy
Preclinical studies
Study | Generation | Costimulatory domain | Transduction method | In vitro efficacy | Impact on normal cells | NSG mice model |
---|---|---|---|---|---|---|
Tashiro 2017 [31] | Second | 4-1BB | Retrovirus | Potent and specific cytotoxicity against CLL-1+ targets | Cytotoxic to mature myeloid cells, sparing myeloid progenitor cells | Significantly prolonged survival |
Laborda 2017 [50] | Second | 4-1BB | Lentivirus | Robust toxicity on AML cell lines and patient-derived AML blast | Minor decrease in CFU-GM, no impact on BFU-E, CFU-GEMM, and HSC; Neutropenia. | Complete elimination of leukemia by day 90 |
Kenderian 2016 [51] | Second | 4-1BB | Lentivirus | Modest effect to primary AML blasts; highly effective to CLL-1+ AML cell lines. | N/A | 100% survival at day 200 in combination with cytarabine while 20% in untreated. |
Wang 2018 [28] | Third | CD28 and 4-1BB | Lentivirus | Specific and strong lysis of AML cell line and primary AML blasts | Eradicating mature granulocytes, variable elimination of progenitors, sparing HSC | Significantly decreased leukemia burden and prolonged survival |
Togni 2018 [52] | Second | 4-1BB | Lentivirus | Dose-dependent killing efficacy | N/A | Significantly prolonged survival with CLL-1 CART-A while not with CART-B |
Clinical trials
Study identifier | ICG136 | ICG144 | NCT03222674 | NCT03631576 |
---|---|---|---|---|
Clinical phase | I | I | I/II | II/III |
Target | CLL-1/CD33 | CLL-1/CD33 | Muc1/CLL-1/CD33/CD38/CD56/CD123 | CD123/CLL-1 |
Generation | Second | Second | Fourth | N/A |
Costimulatory domain | CD28 for CLL-1/4-1BB for CD33 | CD28 for CLL-1/4-1BB for CD33 | N/A | N/A |
Transduction method | Lentivirus | Lentivirus | N/A | N/A |
Patient number | 1 | 1 | 10 | 20 |
Age (years) | 44 | 6 | 2–75 | ≦75 |
Conditioning chemotherapy | FC | FC | N/A | N/A |
CAR-T dose | 7 × 105/kg | 1 × 106/kg/days × 2 days | N/A | N/A |
Study start | N/A | N/A | 2017 | 2018 |
Estimated completion date | N/A | N/A | 2020 | 2021 |
Status | N/A | N/A | Recruiting | Recruiting |
Results | MRD− followed by sibling matched HSCT | complete response, followed by Haplo-HSCT | N/A | N/A |
Adverse events | Grade 1 CRS, pancytopenia | Grade 1 CRS, grade 3 neurotoxicity, pancytopenia | N/A | N/A |