P2, N=60, Active, not recruiting, UNICANCER | Trial primary completion date: Oct 2024 --> Mar 2025

Molecular studies, including western blot analysis and immunocytochemistry, revealed that Isotelekin reduced the expression of iNOS (Inducible nitric oxide synthase), COX-2 (Cyclo-Oxygenase 2), and p-IkBα (Phospho I-kappa-B-alpha), and significantly inhibited the nuclear translocation of NF-κB/p65. Based on these results, Isotelekin at 10 µm in in vitro and at 30 mg kg-1 in in vivo demonstrated strong anti-inflammatory and immunosuppressive therapeutic potential.

MEG3 modulates the TME by affecting TAMs through CSF-1, thereby influencing the balance of Th1/Th2 cells and altering the expression of PD-1/PD-L1s. This study demonstrates that targeting MEG3 is an effective therapeutic strategy for HCC.

Finally, mifamurtide, an immunomodulator acting on TAMs, was evaluated on the most in vitro relevant model: 3D co-culture CH2879 model. Our results showed that it is now possible to develop 3D models that very accurately mimic what is found in vivo with the possibility of evaluating treatments specific to a tumor cell component.

P=N/A, N=80, Recruiting, Istituto Ortopedico Rizzoli | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

TEC mitigates IBD and LPS-induced macrophage inflammation in mice via inhibiting MAPK signaling pathway.

Subsequently, after antagonizing the TLR4 pathway with antagonists (TAK242, PDTC, KG501, SR11302, LY294002), the expression of IL-6, TNF-α, iNOS, and IL-1β mRNA were detected by RT-qPCR. Furthermore, JXY inhibited M1-related molecules such as IL-6, TNF-α, iNOS, and IL-1β after antagonizing the TLR4 pathway. Obviously, JXY could exhibit inhibitory effects on the development of colon tumors in mice with CAC by promoting M1 polarization through TLR4-mediated signaling and impeding M2 polarization of macrophages.

In a murine wound infection with vancomycin-resistant Enterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduce the bacterial load by approximately 10-fold, which is abolished by macrophage depletion...Other Src kinase inhibitors such as DMAT and tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearance in vitro and in vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infections through multiple mechanisms and could be used to boost the host innate immunity to combat drug-resistant bacterial infections.

P1, N=48, Active, not recruiting, Carisma Therapeutics Inc | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2023 --> Dec 2024

Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing.

P=N/A, N=80, Recruiting, Istituto Ortopedico Rizzoli | Trial primary completion date: Dec 2023 --> Jun 2024

P1/2, N=46, Active, not recruiting, Lokon Pharma AB | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Aug 2023

P2, N=60, Active, not recruiting, UNICANCER | Recruiting --> Active, not recruiting

P2, N=60, Recruiting, InSilico Medicine Hong Kong Limited | Phase classification: P2a --> P2

P2, N=60, Recruiting, InSilico Medicine Hong Kong Limited | Not yet recruiting --> Recruiting | Phase classification: P2a --> P2

P1, N=24, Recruiting, SIRPant Immunotherapeutics, Inc. | Not yet recruiting --> Recruiting

Conclusion SMART101 is the first-generation of allogeneic TLP cell therapy obtained from Smart Immune's proprietary GMP manufacturing platform. The duration and the depth of T cell immunodeficiency post haplo PTCy HSCT is expected to be significantly reduced by the infusion of SMART101 thereby decreasing the non-relapse mortality and morbidity rates and thus improving the overall clinical outcome of this therapy.

Tumor response, including abscopal response, is evaluated by Lugano criteria or other Workgroup criteria as appropriate for the tumor type at the end of the DLT-period (Day 30), Week 12 and per SOC thereafter. Serial blood samples and a tumor biopsy before and 16 days after treatment are collected for multi-parameter analyte detection including pro-inflammatory cytokines, multiplex flow cytometry, scRNA sequencing, and ctDNA analysis to investigate pharmacodynamics and mechanism of action.

We provide experimental evidence that the synergic use of an anti-IL-10 antibody in combination with mifamurtide causes a significantly increased mortality rate in highest-grade OS cells and lower metastasis in an in vivo model compared with mifamurtide alone. Overall, our data suggest that mifamurtide in combination with an anti-IL-10 antibody could be proposed as a new treatment protocol to be studied to improve the outcomes of OS patients.

The results of flow cytometry showed that DcR3 could reverse the promoting effect of miR-148b on the CD86/CD163 ratio of macrophages (P<0.05). miR-148b inhibits the expression of DcR3, thereby inhibiting M2 polarization in LPS-stimulated macrophage cells.

Moreover, treatment of normal macrophages with CYLD siRNA enhanced activation of STAT-1, leading to increases in expressions of maturation markers and IL-6 production as well as suppression in cell apoptosis and phagocytosis, while macrophage phagocytosis from AML M4/M5b was higher than that from healthy controls upon CYLD siRNA transfection through STAT1 signalling. In conclusion, the inhibitory effects of CYLD on macrophage functions are expected to affect the immune response in AML.

P1, N=24, Not yet recruiting, SIRPant Immunotherapeutics, Inc.

P=N/A, N=80, Recruiting, Istituto Ortopedico Rizzoli | Trial completion date: Dec 2021 --> Jun 2024 | Trial primary completion date: Dec 2021 --> Dec 2023

SMART101 is the first-generation of allogeneic T lymphoid progenitor cell therapy obtained from Smart Immune's proprietary ProTcell platform, the first scalable progenitor T-cell manufacturing system in clinics. Notch, Thymus, Post-transplant, Allogeneic hematopoietic stem cell transplant

In addition, studies are underway exploring the therapeutic efficacy of the TLR-stimulated BMDM using a murine mammary carcinoma model. The ultimate goal of this project is to produce a computational model capable of predicting how BMDM respond to TLR stimulation and to use the model to predict the anti-tumor efficacy of the BMDM.

Overall, T7-Exo/siGalectin-9 promotes macrophage repolarization and restricts the immunosuppression of GBM, thus providing novel insights into and drug delivery system of immunotherapy for GBM.

AFP could also enhanced the migration ability of macrophages and inhibited the apoptosis of HCC cells when co-cultured with M1-like macrophages. AFP is a pivotal cytokine that inhibits macrophages to phagocytize HCC cells.

In the LOKON002 phase I/II clinical trial (NCT03225989), therapy with LOAd703 (delolimogene mupadenorepvec) is investigated in combination with gemcitabine-based chemotherapy in patients with advanced cancer. In conclusion, LOAd703 therapy in combination with chemotherapy generated an inflamed tumor microenvironment in tumors that are normally seen as immunologically “cold”. Hence, LOAd703 may be able to prime tumors for immune checkpoint inhibitors or other immunotherapies, such as adoptive T or NK cell transfer.

Partial response (PR) was achieved in two patients with pancreatic cancer treated at the highest LOAd703 dose level in combination with gemcitabine and nab-paclitaxel. No association between adverse events and response was identified. Anti-adenoviral antibody levels (IgG), which increased in all patients, could not be related to indices of clinical benefit.Based on the safety of LOAd703 at all dose levels studied, as well as evidence of objective clinical activity in patients with advanced pancreatic cancer, further disease-directed studies of intratumoral administration of LOAd703 are warranted.

We have previously developed CT-0508, a chimeric antigen receptor macrophage (CAR-M) targeting HER2 which showed efficacy in a variety of pre-clinical models and is currently in a Phase I clinical trial for patients with HER2+ solid tumors. The presented results demonstrate that CT-1119, an autologous human anti-mesothelin CAR-M, can cause phagocytosis, tumor cell killing, and pro-inflammatory cytokine release in response to stimulation with mesothelin. These results show that CAR-M is a feasible approach for the treatment of mesothelin expressing sold tumors via the potential for induction of a systemic anti-tumor response.

Ovarian cancer is commonly treated with debulking surgery, followed by a combination of a taxane and a platinum-based chemotherapy. This effect was confirmed in vivo, in which the combination therapy had a better tumor control than the other treatment groups. A clinical trial is ongoing to confirm the effect of adding LOAd703 to different treatment regimes in ovarian cancer (NCT03225989).

We are also performing multiplex analysis of proteomic changes in infected tumor cells using the OLINK® TARGET 96 assay. Finally, we willconfirm the effect of LOAd703 in vivo in a murine xenograft model for STS.

A novel series of flavonoids were synthesized from the natural flavonoid, hesperetin, including 17 new compounds. Screening tests indicated that most of these compounds reduced NO production in LPS-stimulated murine macrophages at concentrations of 15 to 60 μM, and the inhibition generally increased in a dose-dependent manner. Some compounds showed different degrees of cytotoxicity on the human TBNC cell lines, SUM 149.

Our results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics-glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.

Furthermore, increased production of CC chemokine ligand 2 (CCL2) and CCL5 by macrophages elevated ovarian cancer-mesothelial cell adhesion. These findings imply that macrophages may play a significant role in ovarian cancer-mesothelial cell adhesion by inducing the mesothelial expression of adhesion-related genes via the JNK and Akt pathways.

Overall, these results suggest, for the first time, that conjugated derivatives of phenolic acids seem to be more effective at protecting neurons from inflammation damage and oxidative stress. Further in vivo studies are warranted.

Importantly, administration of UBC9 inhibitor, 2-D08, promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade (ICB) therapy. Together, our results demonstrated that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs via promoting STAT4 mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Repolarization of macrophages attracted to the site of ablation to a M1 phenotype promotes local tumor con- trol, reducing the development of metastatic disease and pro- longing survival in a mouse model of bladder cancer.

These results suggest that the Apis mellifera anatoliaca venom does not have anticancer drug candidate potential, whereas it can efficiently be used against inflammatory and autoimmune disorders. To our knowledge, this is the first study to specifically examine the effect of anti-inflammatory activity of Apis mellifera anatoliaca venom on macrophages.

Inhibition of TGFβ signaling in TEX with mRER ameliorated these pro-tumor activities. Silencing of TGFβ emerges as a critical step in suppressing pro-angiogenic functions of TEX in HNSCC.

P1, N=48, Recruiting, Carisma Therapeutics Inc | N=18 --> 48 | Trial completion date: Feb 2023 --> Dec 2024 | Trial primary completion date: Feb 2022 --> Jul 2023