Table 1.
Published preclinical evidence supporting combination regimens incorporating immune checkpoint inhibitors in pancreatic cancer
| ICI | Non-ICI systemic therapy | Source | Refs. |
|---|---|---|---|
| Anti-PD-L1 mAb IP 0.3 mg 3× per week ×4 weeks | Gemcitabine IP 60 μg/g D1, 4, 7, 10, and 13 ×2 weeks | Mice PAN 02 | [4] |
| Anti-PD-L1 mAb IP 160 μg every 48 h up to 6 days | CXCL12 inhibitor (AMD3100) osmotic pump at 30 mg/mL or 90 mg/mL up to 6 days | Mice KPC | [32] |
| CTLA-4 inhibitor IP 250 μg/dose or PD-1 inhibitor IP 200 μg/dose every 4–5 days | CSF1 neutralizing antibody IP every 4–5 days (1 mg for first dose then 0.5 mg) or CSF1R inhibitors 800 mg/kg in chow | Mice KRAS-INK | [17] |
| PD-1-CD28 fusion receptor-transduced OT-1 T-cells IV cocultured for 48 h at a ratio 10:1 T-cell/tumor cells | PD-1-CD28 fusion receptor-transduced OT-1 T-cells | Mice PANC 02-OVA | [39] |
| Anti-PD-1 mAb IP 100 μg or anti-PD-L1 mAb IP 100 μg on D3 after inoculation → every 2 weeks | Cyclophosphamide 100 mg/kg IP X1 on D3 after inoculation + GVAX SC in 3 limbs (0.1 mL) on D4, 7, 14, and 21 | Mice PANC 02 | [28] |
| Anti-PD-1 IP 200 μg D0, 3, 6, 9, 12, 15, 18, and 21 and/or anti-CTLA-4 IP 200 μg D0, 3, and 6 after enrollment | Gemcitabine + nab-paclitaxel IP 120 mg/kg D1 and CD40 agonistic antibody IP 100 μg D3 | Mice KPC | [42] |
| Anti-PD-L1 mAb IP 10 mg/kg twice weekly on D7 or D14 after inoculation ×6 doses | CD40 agonistic antibody IP 3 mg/kg once weekly on D7 after inoculation ×4 doses | Mice PAN 02 | [41] |
| Anti-CTLA-4 mAb IP 250 μg or anti-PD-1 mAb IP 200 μg every 4–5 days | FAK inhibitor (VS-4718) oral gavage 50 mg/kg twice daily and/or gemcitabine IV 25 mg/kg every 4–5 days | Mice KP, KPPC | [18] |
| Anti-PD-1 mAb IP 20 mg/kg every 3 to 4 days on D3 after inoculation | NaHCO3 oral drinking water 200 mM ad lib 3 days prior to inoculation | Mice PANC 02 | [25] |
| Anti-PD-1 mAb IP 10 mg/kg twice weekly | CXCR2 SM oral 100 mg/kg twice daily | Mice KPC | [36] |
| Anti-PD-L1 mAb IP 200 μg twice weekly up to D21 | Local RT 20 Gy on D0 and 15 Gy on D7 + 2 × 106 MC57-SIY cells (vaccine) on D0 with 2 SC doses of boosted vaccine (10 μg SIY peptide and 20 μg poly I:C each) on D7 and D21 | Mice PANC02-SIY | [30] |
| Anti-PD-L1 antibody 200 μg/mouse) every 2 days ×10 days | MLL1 inhibitor (verticillin A) 0.5 mg/kg body weight every 2 days ×10 days | Mice PANC02-H7 | [19] |
| Anti-PD-1 mAb IP 200 μg every 2 days ×10 days | Ruxolitinib oral gavage 50 mg/kg starting on D5 after inoculation daily ×10 days | Mice PANC02-H7 | [21] |
| Bispecific PD-L1 and CXCL12 trap IV 50 μg plasmid/mice every 2 days ×4 doses starting on D13 after inoculation | Bispecific PD-L1 and CXCL12 trap | Mice KPC-RFP/luc | [33] |
| Anti-PD-1 mAb IP 200 μg every 3 days as needed ×18 days starting on D7 after inoculation | MEK inhibitor IP 1 mg/kg daily ×18 days starting on D7 after inoculation | Mice 65 671 | [22] |
| PD-1 or PD-L1 inhibitor IP (dose not specified) once weekly 1 week after inoculation | IL-18 inhibitor (IL-18BP) IP (dose not specified) once weekly 1 week after inoculation | Mice PANC 02-luc | [35] |
| Anti-PD-L1 mAb IP 200 μg/mouse 3× per week ×2 weeks | Anti-IL-6R mAb IP 200 μg/mouse 3× per week ×2 weeks | Mice KPC-BRCA 2, MT5, PANC 02, or KPC-luc | [34] |
| Anti-PD-L1 mAb IP 200 μg every 1 and 3 days after PolyICLC injection | mAb-AR20.5 IP 50 μg D7, 17, 27 and 37 + PolyICLC IP 50 μg D8, 13, 18, 23, 28, 33, 38, and 43 | Mice PANC02.MUC1, KPC.MUC1 | [43] |
| Anti-PD-1 mAb IP 10 mg/kg 2× per week on D10 after inoculation | Anti-BAG3 antibody IP 20 mg/kg 3× per week on D10 after inoculation | Mice mt4-2D | [20] |
| A12-IFNγ (IP 5 μg/mouse daily ×18 days) or B3-IL2 (IP 1 μg/mouse daily ×18 days) fusion compounds | A12-IFNγ: single-domain antibodies against PD-L1 fused with IFNγ B3-IL2: single-domain antibodies against PD-L1 fused with IL-2 |
Mice PANC 02, KPC, KPC organoids | [38] |
| Anti-PD-1 mAb IP 125 μg ×3 doses or 200 μg every 3 days or anti-CTLA-4 mAb IP 200 μg every 3 days on D7 after inoculation | CCK-A receptor inhibitor (L364,718) ILP 4 mg/kg 3× per week or CCK-B receptor inhibitor (proglumide) oral 30 mg/kg daily on D7 after inoculation | Mice PANC 02, mT3-2D | [23] |
| Neoadjuvant anti-PD-1 mAb IP 150 μg every 3 days ×3 doses starting 20 days after electroporation | Neoadjuvant gemcitabine IP 100 mg/kg every 3 days ×3 doses (starting 20 days after electroporation) followed by surgical resection on D8 followed by adjuvant gemcitabine weekly ×5 doses or anti-CD96 mAb IP 250 μg twice weekly ×6 doses + gemcitabine weekly ×7 doses | Mice transgenic (KrasG12V, myrAkt2, and SB13 plasmids and Cre recombinase | [15] |
ICI immune checkpoint inhibitor, PD-L1 programmed death ligand 1, mAB monoclonal antibody, IP intraperitoneal, D day, CXCL12 chemokine (C-X-C motif) ligand 12, CTLA-4, cytotoxic T-lymphocyte associated protein 4, PD-1 programmed cell death protein 1 receptor, CSF1/CSF1R colony-stimulating factor 1/colony-stimulating factor 1 receptor, OT-1 ovalbumine, GVAX allogeneic pancreatic tumor cells transfected with granulocyte–macrophage colony-stimulating factor (GM-CSF) gene, SC subcutaneous, FAK focal adhesion kinase, IV intravenous, CXCR2 C-X-C chemokine receptor type 2, RT radiation therapy, Gy gray, MLL1 mixed-lineage leukemia 1, MEK mitogen-activated protein kinase (MAPK) kinase; IL-18 interleukin 18, IL-6R interleukin 6 receptor, mAb-AR20.5 anti-MUC1, PolyICLC toll like receptor-3 ligand, BAG3 Bcl-2-Associated athanoGene 3, IFNγ interferon-γ, CCK cholecystokinin