Table 1 Immunotherapeutic combination strategies in CRC organoid model
From: Challenges in validation of combination treatment strategies for CRC using patient-derived organoids
Drug Combination | Model Used | Results | Reference |
|---|---|---|---|
CDK4/6 inhibitor (trilaciclib or palbociclib) + anti-PD1 | Patient and murine-derived organotypic tumor spheroids | Greater killing effect, validated in partially anti-PD1 responder (MC38) and anti-PD1 resistant (CT26) mouse models | Deng et al. [132] |
DKK1 inhibitor + anti-PD1 | CRC PDOs model | Increased apoptotic cell proportion and improved response to anti-PD1 | Sui et al. [133] |
Atractylenolide I + anti-PD1 | CRC PDOs model | Enhanced MHC-I-mediated antigen presentation, T cell infiltration, and cytotoxicity, strengthening anti-PD-1 efficacy | Xu et al. [134] |
anti-MICA/B + anti-NKG2A + IL15 | CRC tumor spheroids with T and NK cells | Anti-MICA/B and anti-NKG2A was synergistic and enhanced immune-dependent destruction of tumor spheroid. | Coureau et al. [139] |
IFN-α/β and TNF-α + anti-PD1 | CRC PDOs model with MDSCs | Increased immunogenic organoids cell death following anti-PD-1 therapy | Chen et al. [140] |
CD70-CAR-NK cells + IL-15 | PDOs co-cultured with CAFs | Effective eradication of low- and high-expressing CD70 + tumor cells and CAFs | Van den Eynde et al. [119] |
Ferroptosis induction (Withaferin A) + PD-1 inhibitor + CXCR2 inhibitor (SB225002) | CRC organoids in immunocompetent mice | Effective for CRC liver metastasis inhibition, primary CRC tumor resistant | Conche et al. [161] |
EGFRxLGR5 bispecific antibody (MCLA-158) | CRC PDOs and PDX orthotopic CRC model | Lower IC50 on tumor PDOs, minimal toxicity on adjacent healthy mucosal tissue PDOs, greater tumor reduction in vivo | Herpers et al. [147] |
Bispecific EGFRxHER3-targeting antibody + trastuzumab | CRC cell line spheroids and PDOs | Efficacy demonstrated by CellTiterGlo assays on different CRC models | Rau et al. [150] |
Cibisatamab + WNT/β-catenin inhibitors (LGK-974 and compound 21) | T cell and CRC PDOs co-culture systems | Increased drug sensitivity to cibisatamab, overcoming resistance due to CEA heterogeneity | Gonzalez-Exposito et al. [152] |
SLC25A22 knockout + anti-PD1 | CRC organoids with APC-KRAS mutations in immunocompetent mice | Reversed KRAS-mediated immunosuppressive phenotype, enhanced T cell activation, and synergy with anti-PD1 therapy | Zhou et al. [163] |