P1/2, N=181, Recruiting, Faron Pharmaceuticals Ltd | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Apr 2025

Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs.

P1/2, N=181, Recruiting, Faron Pharmaceuticals Ltd | Trial primary completion date: Dec 2023 --> Dec 2024

Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.

P1/2, N=216, Completed, Faron Pharmaceuticals Ltd | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Oct 2023

We further showed that bexmarilimab was most efficacious in macrophages with low baseline IFN signaling, as chronic IFNγ priming abolished bexmarilimab-induced TNFα release. These results highlight an approach to target immunologically cold tumors and to increase the likelihood of their subsequent response to immune checkpoint inhibitors.

Treatment of AML bone marrow cells with BEX alone or in combination with azacitidine/venetoclax results in enhanced antigen presentation capacity and increased activation markers on effector T cells with synergistic effect on cell death. Additional clinical and pharmacodynamic data of the completed Ph1 of the study will be presented during the meeting. Ph2 of BEX plus azacitidine will open in the 2nd half of 2023 in HMA-failed r/r AML and/or higher risk MDS patients.

P1/2, N=216, Active, not recruiting, Faron Pharmaceuticals Ltd | Trial primary completion date: Nov 2024 --> Sep 2023

Conclusions Bexmarilimab demonstrates promising anti-tumour activity as a monotherapy in several refractory solid tumours. A dose of 1mg/kg Q3W is considered feasible for further monotherapy studies in solid tumors.

P1, N=0, Withdrawn, The University of Texas Health Science Center at San Antonio | N=36 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=216, Active, not recruiting, Faron Pharmaceuticals Ltd | Recruiting --> Active, not recruiting | N=700 --> 216

Treatment of AML bone marrow cells with BEX alone or in combination with azacitidine/venetoclax results in enhanced antigen presentation capacity and increased activation markers on effector T cells with synergistic effects (4). The initial data show that BEX treatment is well-tolerated without additional toxicity to standard treatment. Preliminary efficacy shows 3 responses out of 5 patients in the first dose cohort. The study is ongoing.

Cisplatin suppressed both overall and EGF-specific endocytosis in TAMs by bidirectional mode: suppression of positive regulators and stimulation of negative regulators of endocytosis, with strongest effect on synaptotagmin-11 (SYT11), confirmed in patients with breast cancer. Our data demonstrate that synergistic action of cytostatic agents and innovative immunomodulators is required to overcome cancer therapy resistance.

PD-L1/Clever-1 IHC staining ratio may be used to predict bexmarilimab responding patients. These patients have a low PD-L1 staining and low IFNg levels as reported previously, and are often refractory to checkpoint inhibitors and other T cell activating agents. Bexmarilimab provides a novel therapy option for a tumor group that is otherwise poorly responsive to immune therapies.

The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity...Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.

P1, N=36, Not yet recruiting, The University of Texas Health Science Center at San Antonio | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

By using TCGA and THPA databases, we validated 2 genes, SERPING1 and GIMAP4, that were related to the early detection of bone metastasis in BC. 2 abnormally expressed hub genes could play a pivotal role in the breast cancer with bone metastasis by affecting bone homeostasis imbalance in the bone microenvironment.

To study PTC, we used a mouse model in which expression of BRAF was specifically switched on in thyrocytes by doxycycline administration...Lastly, we demonstrated the presence of CD206+/STABILIN-1+ macrophages in human thyroid pathologies. Altogether, we revealed the recruitment of immunosuppressive STABILIN-1 macrophages in a PTC mouse model and the interest to further study this macrophage subpopulation in human thyroid tissues.

P1, N=36, Not yet recruiting, The University of Texas Health Science Center at San Antonio | Initiation date: Sep 2022 --> Dec 2022

In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.

Cell-to-cell interaction modeling and assays in vitro demonstrated the role of the inflammatory CXCL12-CXCR4 axis in CAF-myeloid cell crosstalk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12-CXCR4 axis acquire pro-tumorigenic LAM capacities to support an immunosuppressive microenvironment.

The association of intratumoral Clever-1 + macrophages with better prognosis might stem from the function of Clever as a scavenger receptor that modulates tumor stroma. The association of Clever-1 + macrophages with high number of TILs and better prognosis indicates that immunosuppression by M2 macrophages is not necessarily dampening adaptive immune responses but instead keeping them in control to avoid excess inflammation.

In vivo, bexmarilimab showed dose-dependent duration of monocyte Clever-1 receptor occupancy in cynomolgus monkeys but did not induce a cytokine storm up to a dose of 100 mg/kg. In conclusion, these data support the clinical development of bexmarilimab for the restoration of immune response in cancers.

Progenitor-mediated increase in lymphatic vessels can enhance immunosuppression by physical removal of stimulatory immune cells. Thus, targeting Th2 pathways might simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that ultimately promote tumor spread.

P1, N=36, Not yet recruiting, The University of Texas Health Science Center at San Antonio | Trial completion date: Jan 2025 --> Dec 2025 | Initiation date: Apr 2022 --> Sep 2022 | Trial primary completion date: Jan 2024 --> Dec 2024

Samples were treated for 48h with bexmarilimab alone, or in combination with azacytidine and/or venetoclax. Furthermore, NK and CD8+ T cells showed decreased PD-1 and increase of activation markers. These results confirm the therapeutic potential of bexmarilimab in myeloid malignancies and await further validation in clinical trials.

P1, N=36, Not yet recruiting, The University of Texas Health Science Center at San Antonio | Initiation date: Jan 2022 --> Apr 2022

Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.

P1, N=36, Not yet recruiting, The University of Texas Health Science Center at San Antonio

The combination of intratumoral CLEVER-1 lymphatic vessel + CD68 TAM was associated with poor DSS in stage I-IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1 lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.

Our data are consistent with previous studies with respect to the lack of association of renal dysfunction with serum proteins and translocations. However, we observed interesting associations with BRAF mutations and a trend with KRAS mutations, suggesting a role in disease pathogenesis beyond driving tumorigenesis. Additionally, we detected expression changes with several genes involved in inflammatory responses.

Our results reveal a non-redundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in metastatic cancer patients.

Four genes coexpressed with M2 macrophages were associated with high levels of infiltration of M2 macrophages. Our findings may provide significant candidate biomarkers for the treatment and monitoring of melanoma.

In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.