Table 1.
Target agents directed against TME or immunotherapies under investigation in PDAC.
| Name | Type/structure | Mechanism of action | Effect |
|---|---|---|---|
| ALT-803 | Fusion protein | Binds IL-2/IL-15 receptor beta common gamma chain (IL-2R beta gamma) receptor on natural killer (NK) and CD8+ | Activation and increase of NK cell memory CD8+ levels |
| AM0010 | Covalent conjugate of recombinant human interleukin-10 (IL-10) and polyethylene glycol (PEG) | Activates cell-mediated immunity against cancer cells by stimulating the CD8+ differentiation and expansion | Potential antifibrotic, anti-inflammatory, immunomodulating, and antineoplastic activities |
| AMG 820 | Fully human monoclonal antibody (IgG2) | Against the colony-stimulating factor-1 (CSF-1 or M-CSF) receptor c-fms (or CSFR1) | Suppresses recruitment and activation of TAMs |
| Anakinra | Recombinant human nonglycosylated IL-1 receptor antagonist | Blocks IL-1 activity | Inhibition of VEGF, TNF-α, and IL-6 cascade resulting in inhibition of tumor angiogenesis |
| Atezolizumab | Humanized, Fc optimized | Binds to PD-L1, blocking its binding to and activation of PD-1 on activated T-cells | Enhancement of T-cell-mediated immune response and reversal of T-cell inactivation |
| Avelumab | Human monoclonal antibody (IgG1) | Binds to PD-L1 preventing interaction with PD-1 | May restore immune function activation of cytotoxic T lymphocytes |
| BL-8040 | Short peptide | Binds to the chemokine receptor CXCR4, preventing the binding of stromal-derived factor-1 to the CXCR4 receptor | Decreases tumor cell proliferation and migration |
| CCX872-B | Small molecule | Human C-C chemokine receptor type 2 (CCR2) antagonist | Inhibition of both CCR2 activation and CCR2-mediated signal transduction |
| CD8 + NKG2D + AKT cell | Cells | Human CD8+ tumor specific engineered to express the natural killer cell-activating receptor group 2D (NKG2D) and the serine/threonine kinase AKT | Potential immunomodulating and antineoplastic activities |
| CRS-207 | Recombinant Listeria-based cancer vaccine expressing human mesothelin | Listeria invades professional phagocytes within the immune system and expresses mesothelin, activating a cytotoxic T lymphocyte response against mesothelin-expressing tumor cells | Potential immunostimulatory and antineoplastic activities |
| Durvalumab | Fc-optimized monoclonal antibody | Binds to PD-L1 blocking its binding to and activation of PD-1 expressed on activated T-cells | Reverses T-cell inactivation and activates the immune system to exert a cytotoxic T lymphocyte response against PD-L1-expressing tumor cells |
| Galunisertib | Small molecule | Antagonist of TGF-β receptor type 1 (TGFBR1) | Prevents the activation of the TGF-β-mediated signalling pathways inhibiting tumor proliferation |
| GVAX | Allogeneic cancer vaccine composed of lethally irradiated whole melanoma cancer cells that are genetically modified to secrete the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor | Stimulates the body's immune system against tumor cells | Enhances the activation of dendritic cells, promotes antigen presentation to both B- and T-cells, and increases IL-2-mediated lymphokine-activated killer cell function |
| iAPA-DC/CTL | A cell-based product composed of dendritic cells (DCs) pulsed with tumor-associated antigens and devoid of the inhibitory effect of antigen presentation attenuators (iAPA) combined with cytotoxic T lymphocytes | Prevents the expression of APA genes and inhibits attenuation of antigen presentation | Potential immunostimulating and antineoplastic activities |
| Ibrutinib | Small molecule | Binds to and irreversibly inhibits BTK activity | Prevents both B-cell activation and B-cell-mediated signalling leading to growth inhibition of the malignant B-cells overexpressing BTK |
| IDO-1 inhibitor | Small molecule | Targets and binds to indoleamine 2,3-dioxygenase 1, a cytosolic enzyme responsible for the oxidation of tryptophan into the immunosuppressive metabolite kynurenine | Restores and promotes proliferation and activation of various immune cells and causes a reduction in Tregs |
| Ipilimumab | Recombinant human monoclonal antibody (IgG1) | Binds to CTLA4 expressed on T-cells | Inhibits the CTLA4-mediated downregulation of T-cell activation leading to a cytotoxic T lymphocyte-mediated immune response |
| M7824 | Bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-β receptor II | “Trap” for all three TGF-β isoforms | Suppressed tumor growth and metastasis |
| MCS110 (Lacnotuzumab) | Humanized monoclonal antibody | Binds to M-CSF and blocks M-CSF-mediated signalling through the M-CSF receptor CD116 | Antineoplastic activities |
| Nivolumab | Fully human monoclonal antibody (IgG4) | Binds PD-1 and blocks its activation by PD-L1 | Activation of T-cell immune responses against tumor |
| Pamrevlumab | Humanized monoclonal antibody | Binds to connective tissue growth factor (CTGF) preventing the binding to the receptor and its subsequent activation | May prevent and reverse fibrosis; prevents tumor cell proliferation in CTGF-expressing tumor cells |
| PDR 001 (Spartalizumab) | Humanized monoclonal antibody | Directed against the negative immunoregulatory human cell surface receptor programmed death-1 | Prevents PD-1-mediated signalling and results in both T-cell activation and the induction of T-cell-mediated immune responses against tumor cells |
| PEGPH20 | Recombinant form of human hyaluronidase | Degrades hyaluronic acid- (HA-) coating tumor cells | Inhibition of tumor cell growth, lowering of the interstitial fluid pressure and allowing better penetration of chemotherapeutic agents into the tumor bed |
| Pembrolizumab | Humanized monoclonal immunoglobulin antibody (IgG4) | Directed against PD-1 | Restores T-cell activation and immune response |
| Pexidartinib | Small molecule | Binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R), and FMS-like tyrosine kinase 3 (FLT3) | Inhibition of tumor cell proliferation and downmodulation of macrophages, osteoclasts, and mast cells |
| RO7009789 | Recombinant monoclonal antibody | Binds to CD40 on a variety of immune cell types | Activation of antigen-presenting cells (APCs), B-cells, and T-cells, resulting in an enhanced immune response |
| Tremelimumab | Human immunoglobulin monoclonal antibody (IgG2) | Directed CTLA4 | A cytotoxic T lymphocyte immune response against cancer cells |
| Vactosertib | Small molecule | Inhibitor of the serine/threonine kinase TGFBR1 also known as activin receptor-like kinase 5 (ALK5) | Inhibits the activity of TGFBR1 and prevents TGF-β/TGFBR1-mediated signalling and suppresses tumor growth |
| VCN-01 | Adenovirus | Replication-competent adenovirus encoding the human glycosylphosphatidylinositol-anchored enzyme PH20 hyaluronidase | Potential antitumor activity |
| γδ T-cell | Cells | Secrete interferon-gamma | Direct killing of tumor cells, activation of cytotoxic T lymphocyte response against tumor cells |