Table 2.
Summary of 14 completed clinical trials of solid tumour CAR-T therapy: scFv affinity vs clinical efficacy
| Target | Target binding Domain | ICD | In vitro or Preclinical | Clinical trials |
|---|---|---|---|---|
| FRα (folate binding protein) | scFv based on MOv18 KD: ∼0.2 nM (Ref. 210) | FceRIγ | Dual specific T cells (allo-TCR and FRα CAR) inhibited tumour growth (Ref. 211) | NCT00019136 No reduction in any of 12 patients (Ref. 212) |
| GD2 | scFv from mAb Hu3F8 (Ref. 213) KD: 11 nM | CD28-BB-CD3ζ | GD2-specific chimeric antigen receptor-modified T cells for the treatment of refractory and/or recurrent neuroblastoma in pediatric patients (clinical trial show only SD in 4/10 patients. Other 6 died due to PD | NCT02765243 4/10 SD for 1 yr DOI:CSBOLDSTART CSBOLDEND10.21203/rs.3.rs-803629/v1 |
| scFv from 14.G2a (Ref. 213) KD: 77 nM | CD3ζ | EBV-CTL expressing 14.G2a-CD3ζ CAR were expanded and maintained long-term in the presence of EBV-infected B cells (Ref. 214). However, CAR-ATC (activated general T cells) were not expanded by GD2. | NCT00085930: Initial report (Ref. 148) found CAR-CTL (EBV-CTL transduced with CAR) generated better expansion than CAR-ATC, but a later report (Ref. 215) showed that CAR-ATC persists 4 years. Clinical outcome: 3 CR (2 sustained for > 4 years), 1PR, 1SD out of 11 patients. | |
| CD28-OX40- ζ | 14g2a-CD28-OX40-Z Construct Signalling Induces Sustained Clonal Expansion (Ref. 149) | NCT01822652 (Ref. 216). 5/11 SD, among the SD, 2 became CR after salvage treatment. Higher dose plus chemo and PD1 extended survival. | ||
| KM8138 (Ref. 217) KD: 149 nM | CD28- ζ | NCT02761915 (Ref. 218): No response in 12 patients, but some response in bone marrow disease for 1 patient. | ||
| CD171 (L1-CAM) | CE7 scFv KD: 0.01 nM (patent US7354762) | CD3ζ | NCT00006480 (Ref. 219): 1 PR/ 6 patients but only for 56 days. CAR-Ts disappears in a week in high tumour burden and 42 days in limited tumour burden. | |
| CEA | scFv based on hMN14 KD: 3.4 nM (Ref. 220) | CD28-ζ | NCT01373047: Hepatic artery injection of CAR-Ts with (3) or without (3) IL2 support. 1 SD/6 (Ref. 221) | |
| scFv based on MFE23 KD: 2.3 nM (Ref. 222) | CD3ζ | NCT01212887 (Ref. 223). No clinical responses, Low persistence of CAR-Ts | ||
| Claudin 18.2 | hu8E5 scFv (Ref. 224) EC50: 45 nM | CD28-ζ | NCT03159819 (Ref. 225). 1CR, 3PR, 5SD/12 | |
| C-Met | scFvof Onartuzumab KD: 1.2 nM (Ref. 226) | 4–1BB- CD3ζ | NCT01837602 (Ref. 227). Intratumoural injection of mRNA transduced CAR-Ts, no clinical effects | |
| EGFR | scFv based on E10. KD: 20 nM (in nanobody) (Ref. 228) | 4–1BB- CD3ζ | NCT01869166 (Refs 229, 230). 1 CR, 2 PR out of 28 patients | |
| EGFRvIII | scFv based on 3C10–2173 KD of 2173: 101 nM (Ref. 231) | 4–1BB- CD3ζ | Weak antitumour effects in NSG mice (Ref. 231) | NCT02209376 (Ref. 232). No significant clinical effect |
| GPC3 | scFv of GC33 KD (by us): 1.38 nM | CD28- ζ | 2 PR out of 13 patients (Ref. 233). One patient survive more than 2 years. | |
| PMSA | scFv based on 3D8 KD: 22.5 nM (Ref. 234) | CD3ζ | NCT01929239. 2 PR effect but only last 1–2 months (Ref. 235) | |
| ROR1 | scFv based on UC-961 KD: 2 nM (Ref. 236) | 4–1BB- CD3ζ | NCT02706392 (Ref. 237). Limited mix responses in 2 /5 |