Table 1.
Summary of clinical trials targeting immunosuppression in combination with ICB therapy
| S. No. | Target | Expression | inhibitor | Combination immunotherapy | PDAC Stage | Phase | Clinical outcome | References |
|---|---|---|---|---|---|---|---|---|
| 1 | TGFβR1/2 | CAFs, TAMs, and other immune cells | M7824: PD-L1 Ab fused with TGFβR2-ECD trap | Fusion Monotherapy | Locally advanced PDAC (n = 19 patients) | Phase I | Indications of durable partial response; manageable safety profile | NCT02517398 [121] |
| 2 | TGFβR1 | Galunisertib (LY2157299) | Durvalumab (PD-L1) | Refractory PC (n = 37 patients) | Phase Ib | 1 patient had partial response, 7 patients’ stable disease: and 15 patients’ objective progressive disease. Disease control rate 25%. Median OS = 5.72 months. | NCT02734160 [122] | |
| 3 | TGFβ2 | BCA101: anti-EGFR Ab fused with TGFβR2-ECD | Pembrolizumab (PD1) | Advanced disease refractory to SOC therapies (n = 7 patients) | Phase I | Well tolerated and clinically active as a single agent and with anti-PD1 therapy | NCT04429542 [123] | |
| 4 | TGFβ2 | SHR-1701: PD-L1 Ab fused with TGFβR2 ECD | Fusion Monotherapy | Metastatic/ Locally Advanced PDAC (n = 10 patients) | Phase I | 2 out of 10 patients showed stable disease: manageable safety profile | NCT03710265 [124] | |
| 5 | CSF-1R | TAMs | Cabiralizumab (IgG4 hu-mAb) | Nivolumab (PD1) | Advanced/metastatic PDAC | Phase II | Monocyte depletion but no significant clinical benefit | NCT03336216 [125, 126] |
| 6 | CSF-1R | AMG-820 (IgG2 hu-mAb) | Pembrolizumab (PD1) | Advanced/metastatic PDAC (n = 116 patients) | Phase Ib/II | Immune-related PR in 3 patients and immune-related stable disease in 34 patients | NCT02713529 [127] | |
| 7 | CSF1 | lacnotuzumab | Spartalizumab (PD1) | Advanced/metastatic PDAC (n = 13 patients) | phase Ib/II | Well tolerated; Preliminary anti-tumor activity; Disease control rate = 6/13 PDAC patients | NCT02807844 [128] | |
| 8 | CSF-1R | exidartinib (PLX3397) | Durvalumab (PD-L1) | Advanced/metastatic PDAC (n = 19 patients) | Phase I | Clinical benefit rate at 2 months was 21% in the dose escalation cohort; no unexpected toxicity | NCT02777710 [129] | |
| 9 | CD40 | APCs (DCs), myeloid and B cells | APX005M (sotigalimab) | Nivolumab (PD1) ± Chemo | Metastatic PDAC (n = 30 patients) | Phase I | Tolerable regimen with 58% PR and 30% SD. | NCT03214250 [130] |
| 10 | CD40 | APX005M (sotigalimab) | Nivolumab (PD1) ± Chemo | First line Metastatic PDAC (n = 99 patients) | Phase II | APX005M + Nivolumab and chemo showed OS = 41.3% with median OS = 10.1 mo. The triple combination provided immune markers associated with survival. | NCT03214250 [131] | |
| 11 | CD40 | CDX-1140 | Pembrolizumab (PD1) | Advanced solid malignancies | Phase I | Objective was to find MTD (1.5 mg/Kg) | NCT03329950 [132] | |
| 12 | CXCR4 | Tumor cells, macrophages and MDSCs | BL-8040 | Pembrolizumab (PD1) | Chemotherapy-resistant PDAC (n = 37 patients) | Phase I | Disease control rate (34.5%); and nine patients with SD, and one patient with partial response. | NCT02826486 [133] |
| 13 | CXCR4 | BL-8040 | Pembrolizumab (PD1) | Recurrent and metastatic PDAC (n = 18 patients) | Phase IIb | Results awaited | NCT02907099 [134] | |
| 14 | CXCR4 | LY2510924 | Durvalumab (PD-L1) | Previously treated advanced and metastatic PDAC | Phase I | Disease control rate of 37.5% achieved. | NCT02737072 [135] | |
| 15 | CXCR4 | BMS-936564/MDX1338 (Ulocuplumab) | Nivolumab (PD1) | Previously treated advanced and metastatic PDAC | Phase I/II | Terminated with no clinical outcome | NCT02472977 [135] | |
| 16 | CXCR2 | Neutrophils, macrophage, cancer cells, and ECs | AZD5069 | Durvalumab (PD-L1) | Previously treated metastatic PDAC (n = 23 patients) | Phase II | Well-tolerated regimen with manageable toxicity | NCT02583477 [136] |
| 17 | CXCL12 | Multiple TME compartments | NOX-A12 | Pembrolizumab (PD1) | Pretreated advanced PDAC (n = 9 patients) | Induction of immune response and stable disease in 25% patients, with a consistent safety profile in metastatic microsatellite stable (MSS) patients | NCT03168139; [137] | |
| 18 | FAK | Cancer cells | Defactinib | Pembrolizumab (PD1) ± Chemo | Refractory PDAC (n = 17 patients) | Phase I | Increased CD8 + T cell infiltration, but no PR or CR observed | NCT02546531 [138] |
Abbreviations: TGFβ1/2R tumor growth factorβ 1/2 receptor, CD40 cluster of differentiation 40, CSF1R colony stimulating factor1 receptor, CXCR chemokine receptor, CXCL chemokine ligand, FAK focal adhesion kinase, SOC standard of care