The ability of CO-005 to trigger strong PCCD while preserving conventional immune responses provides a novel and promising approach for CD47-targeted cancer therapy. Its favorable safety profile, observed in both in vitro and ex vivo studies, positions CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments.

P1/2, N=51, Active, not recruiting, Lokon Pharma AB | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2024 --> Dec 2025

These findings demonstrate the preliminary safety, tolerability and manufacturing feasibility of CT-0508 for HER2+ tumors. ClinicalTrials.gov registration: NCT04660929 .

Incubating bone cores with mifamurtide induced a reduction of cellular markers and an increase in bone volume. This 3D bone core model has the potential to investigate osteosarcoma tumor microenvironment and provides a representative model for evaluation of novel therapies.

P1, N=24, Recruiting, SIRPant Immunotherapeutics, Inc. | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Mar 2025 --> Jun 2025

In vivo studies further confirmed the retention capacity and safety of this probiotic-PS complex. Generally, this research presents an effective probiotic encapsulation strategy that could enhance macrophage immune responses, offering novel insights for probiotic-based therapies in major diseases like colon cancer treatment.

Taken together, our results suggest that NE stimulates M2 macrophage polarization by inducing IL-6 secretion from BC cells through a β2-AR-dependent mechanism, which subsequently promotes cancer cell migration. Targeting β2-AR may represent a promising strategy to prevent chronic stress-induced BC metastasis.

This bispecific stimulated robust anti-tumor responses in multiple xenograft models of aggressive B-cell lymphoma. Our approach can be directly applied to other cancers to rapidly discover bispecific antibodies that leverage anti-tumor responses by macrophages or other innate immune cells.

The constructed long-circulating targeted liposomes co-loading DDP and mifamurtide significantly inhibited the cell viability, migration, invasion and cell apoptosis of MG-63 cells, improving the antitumor effect of DDP and mifamurtide in vitro. The constructed liposomal delivery system is suitable for co-loading DDP and mifamurtide to achieve active tumor targeting, supplying a new strategy for the treatment of OS.

P1/2, N=47, Completed, Lokon Pharma AB | Active, not recruiting --> Completed

Additionally, VCPIP1 deficiency promoted the release of inflammatory factors (IL-1β, IL-6, and TNF-α) in RAW 264.7 cells and BMDMs. This study further expands the role of deubiquitinases (DUBs) in inflammation, providing new insights for the prevention and treatment of sepsis, tumors, immune diseases, and other inflammatory reactions.

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.

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.

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.