Table 1.
Examples of current clinical trials targeting TME mechanisms.
| Mechanism of action | Name of drug | target | Phase of trial | Type of cancer | Concomitant therapies | NCB identifier/reference |
|---|---|---|---|---|---|---|
| inducing MHC-I expression - NF-kappa beta stabilization, regulation of NF-kappa beta expression restored IFN signaling | Sodium stibogluconate | SHP2 | 2 | Myelodysplastic Syndromes/Acute Myeloid Leukemia With One of the 65 Defined p53 Mutations | NA | NCT04906031 |
| WNT/beta pathway modulators | DKN-01 | Dickkopf-1 (DKK1) is a modulator of the Wnt and PI3K/AKT signaling pathways | 1, 2 | patients with advanced mismatch repair proficient oesophagogastric cancer | Atezolizumab | NCT04166721 |
| STING agonists | E7766 (eisai) | highly potent STING agonist | 1/1b | patients with advanced solid tumors or lymphomas | NA | NCT04144140 |
| Inhibiting Death Receptor-Mediated Cytotoxicity | IGM-8444 | DR5 (death receptor 5) | 1 | patients with relapsed and/or refractory solid cancers | FOLFIRI Chemotherapy Regimen |
NCT04553692 |
| Inhibiting Granule-Mediated Cytotoxicity | Pre-clinical studies | NA | NA | NA | NA | NA |
| Inhibiting Apoptotic Pathways Bcl-2 inhibitors | BGB-11417 | highly selective Bcl-2 inhibitor | 1 | patients with mature B-cell malignancies | NA | NCT04883957 |
| mutations leading to increased tumor survival - HER2 pathway | pyrotinib | pan-HER2 inhibitor | 2 | HER2-positive Advanced Colorectal Cancer patients | trastuzumab | NCT04380012 |
| mutations leading to increased tumor survival - BRAF mutations | HLX208 | BRAF V600E Inhibitor | 2 | metastatic colorectal cancer patients | NA | NCT05127759 |
| mutations leading to increased tumor survival - EGFR pathway | DZD9008 | selective, irreversible EGFR inhibito | 1/2 | patients with advanced non-small cell lung cancer with EGFR or HER2 mutation | NA | NCT03974022 |
| mutations leading to increased tumor survival - c-KIT pathway | Imatinib | BCR-ABL, c-KIT, PDGFRA | 2 | patients with stage III unresectable and stage IV melanoma with C-KIT gene mutation | Toripalimab | NCT05274438 |
| targeting MDSC cells - phosphatidylinositol 3-kinase (PI3K) delta | IPI-549 | specific PI3K gamma inhibitor | 2 | Patients With Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma | NA | NCT03795610 |
| Adoptive cell therapies: CAR-T | CEA CAR-T cells | CAE + cancer cells | 1,2 | patients with relapsed and refractory CEA+ cancer | NA | NCT04348643 |
| Adoptive cell therapies: CAR-NK | NKG2D CAR-NK | NKG2D | 1 | patients with refractory metastatic colorectal cancer | NA | NCT05213195 |
| Adoptive cell therapies: CAR-P | No studies – pre-clinical | NA | NA | NA | NA | NA |
| Cytokine based therapies | NKTR-214 (Bempegaldesleukin) | CD122-preferential IL2 pathway agonist | 1 | mCRPC patients who received prior secondary androgen receptor signaling inhibitor therapy | Nivolumab, radiation, Stereotactic body radiation therapy (SBRT), CDX-301, Poly-ICLC, INO-5151, | NCT03835533 |
| Chemokine based therapies | Rintatolimod | selective TLR3 agonist, immune response modulator | 1 | patients with early stage triple negative breast cancer | Drug: CyclophosphamideDrug: DoxorubicinDrug: Doxorubicin HydrochlorideDrug: PaclitaxelBiological: Recombinant Interferon Alfa-2b | NCT04081389 |
| inhibiting NO/iNOS pathway | Pre-clinical | NA | NA | NA | NA | NA |
| Inhibition of ARG1/2 activity | Arginase1 peptide: ArgLong2 (169-206) Peptide sequence | Arg-1 inhibitor | 1,2 | patients with polycythemia vera, essential thrombocythemia | Vaccine - PD-L1 peptide: PD-L1 Long (19-27) | NCT04051307 |
| blocking of adenosine pathway - targeting A2A adenosine receptors | ILB2109 | A2AR antagonist | 1 | patients with advanced solid malignancies | NA | NCT05278546 |
| targeting the IDO pathway | Epacadostat | inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1) | 1,2 | patients with metastatic or locally recurrent breast cancer patients | Retifanlimab, SV-BR-1-GM, low dose cyclophosphamide Interferon Inoculation |
NCT03328026 |
| blockade of PGE2 pathway | CR6086 | selective small molecule antagonist of the prostaglandin E2 receptor, EP4 subtype | 1, 2 | patients with pretreated mismatch-repair-proficient and microsatellite stable metastatic colorectal cancer | Balstilimab | NCT05205330 |
| Hypoxia - targeting HIF pathway | DFF332 | HIF-2 blockade | 1 | patients with advanced/relapsed ccRCC and other malignancies with HIF2α stabilizing mutations | RAD001, PDR001, NIR178 |
NCT04895748 |
| exosomes | Mesenchymal Stromal Cells-derived Exosomes with KRAS G12D siRNA | KRAS mutation | 1 | patients with metastatic pancreas cancer with KrasG12D mutation | NA | NCT03608631 |
| Antibodies bi- and tri-specific combinations | FS118 | PD-L1, LAG-3 | 1, 2 | patients with advanced malignancies | NA | NCT03440437 |
| Anti-cancer vaccines | ACIT-1 | Stimulation of tumour antigen-specific T cells to respond and kill cancer cells | 1, 2 | patients with pancreatic and other cancers | NA | NCT03096093 |
| radiation | radiation therapy | numerous targets | 2 | patients with unresectable non-metastatic pancreatic cancer | Gemcitabine, Capecitabine | NCT01972919 |
| nanoparticles | WGI-0301 | Lipid Nanoparticle Suspension of Akt-1 Antisense Oligonucleotide | 1 | patients with advanced solid tumors | NA | NCT05267899 |
| Immune checkpoint molecules - TIM-3 inhibitors | Cobolimab | anti-TIM-3 | 2 | melanoma stage IV patients | TSR-042 | NCT04139902 |
| Immune checkpoint molecules – LAG-3 inhibitors | INCAGN02385 | Anti-LAG-3 | 1, 2 | patients with selected advanced malignancies | INCAGN02390 INCMGA00012. |
NCT04370704 |
| Immune checkpoint molecules – TIGIT inhibitors | COM902 | TIGIT Inhibitor | 1 | subjects with advanced malignancies | COM701 | NCT04354246 |
| Immune checkpoint molecules - CTLA-4, | Tremelimumab | human monoclonal antibody against CTLA-4 | 1, 2 | patients with gastroesophageal cancer and other gastrointestinalmalignancies | Cabozantinib, Durvalumab |
NCT03539822 |
| Immune checkpoint molecules - PD-1 | GLS-010 (zimberelimab) | Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody | 2 | patients with recurrent or metastatic cervical cancer | NA | NCT03972722 |
| Epigenetic mechanisms - HDAC Inhibitors (HDACi) | Chidamide | selective histone deacetylase (HDAC) inhibitor | 1, 2 | patients with advanced cervical cancer | Toripalimab | NCT04651127 |
| Epigenetic mechanisms - Histone Methyltransferase Inhibitors (HMTi/EZH2i | tazemetostat | EZH2 inhibitor or - histone methyltransferase inhibitor | 2 | subjects with relapsed/refractory follicular lymphoma | rituximab | NCT04762160 |
| Epigenetic mechanisms - Histone Reader Protein Inhibitors (bromodomain and extra-terminal domain proteins - BETi) | ZEN-3694 | BET bromodomain inhibitor | 2 | patients with metastatic castration resistant prostate cancer | enzalutamide; pembrolizumab | NCT04471974 |
| Epigenetic mechanisms - DNA methyltransferase inhibitors | Azacitidine, decitabine | demethylation agents | 2 | patients with newly diagnosed acute myeloid leukemia | Several concomitant drugs | NCT03164057 |
| Stromal mechanisms - CAFs targeted therapies | Pritumumab | ecto-domain of vimentin on the surface of cancer cells | 1 | patients with brain cancer | NA | NCT04396717 |