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

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

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

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

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.

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

These findings are independent of patient age, sex, comorbidity score, prognostic models, and vaccination status. The OMST has the potential to assess monocyte reactivity and its implications in a broad range of clinical situations.

Initial treatment in this series of 295 patients with FL included monoclonal antibody + chemotherapy (57%), single-agent rituximab (15%), chemotherapy (2%), radiotherapy alone (8%), and other treatments (6%). Exploratory analysis with WES was performed on 16 FLEP cases and 10 FLLP cases. There were no significant differences in the occurrence of gene mutations between FLEP and FLLP cases in the WES cohort. Only 1 gene, SETD1B, appeared in the WES panel that is not covered in the HemePACT and clinical IMPACT targeted signaling platforms.

Monocytes can differentiate into TAMs under coculture with SKOV3 cells and/or LPA stimulation. The induced TAMs promote SKOV3 cell proliferation and invasion. The cytokine receptor IL-6sR and the JAK-STAT signaling pathway play an important role in the differentiation of monocytes into TAMs.

This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Here, we provide experimental evidence that the addition of an anti-IL-10 antibody to Mifamurtide causes a significant death rate in more aggressive osteosarcoma cells and lower metastasis, compared to Mifamurtide only. In conclusion, considering our data, it could be proposed a new treatment protocol for metastatic osteosarcoma that includes the use of an anti-IL10 antibody integrated with the administration of Mifamurtide to increase its effectiveness in this clinical context.

Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that are not eligible for treatment with the leading clinical benchmark by inducing a robust ADCC response and activating innate and adaptive immunity to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710).

We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

Downregulation of the TF antigen was mainly restricted to the cryptic pool of TF, efficiently preventing phosphatidylserine-dependent TF activation by daunorubicin, and at least partially regulated on the mRNA level in LPS-stimulated monocytes. Our study thus delineates a complex role of thiol isomerases in the regulation of myeloid TF PCA, with PDI being a promising therapeutic target in the management of AML-associated coagulopathies.

P=N/A, N=80, Recruiting, Istituto Ortopedico Rizzoli | Trial completion date: Jul 2020 --> Dec 2021 | Trial primary completion date: Jul 2020 --> Dec 2021

We identified potential immunotherapeutic agents based on prognostic gene signature: hexamethonium bromide and isoflupredone. Several novel candidate drugs were suggested, including human interferon-α-2b, paclitaxel, imiquimod, MESO-DAP1, and mifamurtide. These biomolecules and repurposed drugs may be utilised for prognosis and treatment for better survival.

Preoperatively, all patients received methotrexate, adriamycin, cisplatinum (MAP)...In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months then weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor histologic response (necrosis < 90%) to MAP... In this prospective uncontrolled study with a risk-adapted strategy for non-metastatic osteosarcoma, survival is superior to that of all ISG/GEIS previous series . The 3-year EFS of 71.9% compares favorably with other reports . Pgp+ patients performed well in this study, in which mifamurtide and HDIFO were added after a poor response to MAP.

P2/3, N=225, Active, not recruiting, Italian Sarcoma Group | Trial completion date: Mar 2021 --> Oct 2021 | Trial primary completion date: Mar 2021 --> Oct 2021

TAMs may participate in the malignant progression of osteosarcoma through self-polarization, the promotion of blood vessel and lymphatic vessel formation, immunosuppression, and drug resistance. Besides, various immune checkpoint proteins expressed on the surface of TAMs, such as PD-1 and CD47, provide the possibility of the application of immune checkpoint inhibitors. Several clinical trials have been carried out and/or are in progress. Mifamotide and the immune checkpoint inhibitor Camrelizumab were both found to be effective in prolonging progression-free survival. Thus, TAMs may serve as attractive therapeutic targets. Targeting TAMs as a complementary therapy is expected to improve the prognosis of osteosarcoma. Further efforts may be made to identify potential beneficiaries of TAM-targeted therapies.

Circulating monocytes from PC patients showed constitutive phosphorylation and weaker response to stimuli, indicating aberrant activation and immune suppression. When co-culturing the patient-derived monocytes with cancer cells, they differentiated into macrophages with reduced levels of M1 macrophage marker CD86, suggesting compromised anti-tumour features. The results highlight the need for global management of tumour-associated immune aberrations in PC treatment.

Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple human tumors. RA has been considered as an anti-cancer agent, whereas our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

Consistently, using co-immunoprecipitation (co-IP) and surface plasmon resonance (SPR) approaches, we show that IFI16 is a specific TLR4-ligand and that IFI16/LPS complexes display a faster stimulation turnover on TLR4 than LPS alone. Altogether, our findings point to a novel pathomechanism of inflammation involving the formation of multiple complexes between extracellular IFI16 and subtoxic doses of LPS variants, which then signal through TLR4.

Overall, these data indicated that PD-1 expression was elevated in monocytes from hepatocellular carcinoma patients. In addition, PD-1 monocytes presented a preference toward M2 polarization and had a deficiency in supporting CD8 T cells.

Our analysis further identified a co-regulatory network implicating upstream transcription factors (JUN, NFKBIA) in monocyte-to-M2 differentiation, and activated ligand-receptor interactions (eg, SFTPA1-TLR2, ICAM1-ITGAM) suggesting intratumoral mechanisms whereby epithelial cells stimulate monocyte-to-M2 differentiation. Overall, our study identified the prevalent monocyte-to-M2 differentiation in NSCLC, accompanied by an intricate transcriptional reprogramming mediated by specific transcriptional activators and intercellular crosstalk involving ligand-receptor interactions.

Preoperatively, all patients received MAP (methotrexate, adriamycin, platinum). In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months than weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor response (PR) to MAP...Funding: The Onlus Association “Il Pensatore - Matteo Amitrano”; Fondazione Carisbo Clinical and Translational Research Grant 2019. Clinical trial identification: NCT01459484; Eudract: 2011-001659-36.

MT-6402 delivers a powerful and unique dual mechanism of action. The combination of a PD-L1 specific direct cell kill and redirection of a robust effector T cell response to the tumor has potential benefit in solid tumor indications, including in the relapsed setting, when disease has progressed after checkpoint and/or other therapies.

This study utilized a primary human co-culture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC) and a cannabinoid receptor-2 (CB2) selective agonist, suppress specific monocyte-mediated astrocyte inflammatory responses. In the context of viral-induced chronic neuroinflammation, the findings presented here suggest that cannabinoids via CB2 ligation may have beneficial anti-inflammatory effects.

In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance.

P2/3, N=225, Active, not recruiting, Italian Sarcoma Group, N=373 --> 225