sotuletinib (BLZ-945)

More importantly, we found that Proguanil's inhibitory effect on U87MG cell growth and migration was positively correlated with CSF1R expression, and this effect diminished following CSF1R knockdown and Proguanil demonstrated synergistic effects with CSF1R-targeting positive drugs (BLZ945 and GW2580). Meanwhile, Proguanil targeted CSF1R to inhibit M2-type polarization of tumor-associated macrophages (TAMs) and their proliferation, thus altering the tumor microenvironment while indirectly suppressing the proliferation and migration of U87MG cells. Taken together, these findings suggest that Proguanil may serve as a promising CSF1R antagonist for GBM treatment.

P2, N=28, Terminated, Novartis Pharmaceuticals | N=56 --> 28 | Trial completion date: Jun 2026 --> Feb 2024 | Recruiting --> Terminated | Trial primary completion date: Mar 2025 --> Feb 2024; Study terminated after assessment of potential benefit-risk from available data

P2, N=56, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting

P2, N=56, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human glioblastoma avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for glioblastoma.

The cytoplasm-located BLZ945 prompts its polarization resistance to M2 phenotype in the immunosuppressive microenvironment via inactivating the intracellular M2 polarization signaling pathway. This ARMFUL provides a versatile cell engineering platform to customize multimodal cellular functions for enhanced adoptive cell therapy.

In addition, the BAX/BCL-2 ratio increased in cells treated with pexidartinib and sotuletinib. With the four novel TGCT cell lines, we have an excellent model for further in vitro and in vivo studies.

To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization...Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.

Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuroinflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, blockade of CSF1R combined with inhibition of STAT5 signaling via AC4-130 led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.

We also examined the therapeutic potential of a clinically relevant CSF1R inhibitor (BLZ945) in lung and colon adenocarcinoma-induced experimental MPE...This was because apart from macrophages, CSF1R signals in cancer-associated fibroblasts leading to macrophage inflammatory protein 2 secretion triggered the manifestation of suppressive and angiogenic properties in macrophages upon CXCR2 paracrine activation. Pharmacological targeting of the CSF1/CSF1R axis can therefore be a vital strategy for limiting MPE.

P1/2, N=198, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2022 --> Aug 2022 | Trial primary completion date: Apr 2022 --> Aug 2022

Here, we assessed the lung tumor immune microenvironment in mice treated with BLZ945, a prototypical small molecule CSF1R inhibitor, using single-cell RNA sequencing and mechanistic validation approaches...These cells included IFNγ-producing NK and T cells, and an IL12-producing dendritic cell subset, denoted as DC3, which were all necessary for CSF1R inhibitor-mediated lung tumor control. These data indicate that CSF1R targeting can activate a cardinal crosstalk between cells that are not macrophages and that are essential to mediate the effects of T cell-targeted immunotherapies and promote antitumor immunity.

P1/2, N=198, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages...The antitumor effector CD8 T cells were increased after treatment. This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.

IL-1β-induced SLC7A11 overexpression upregulated PD-L1 and CSF1 through αKG/HIF1α axis, which promoted TAMs and MDSCs infiltration. Interruption of this oncogenic loop may provide a promising therapy strategy for the inhibition of SLC7A11-mediated HCC metastasis.

[C]BLZ945, a CSF-1R PET tracer, was synthesized in high yield and purity. The tracer has high potency for the target, however, future studies are warranted to address non-specific binding and tracer efflux before BLZ945 or derivatives could be translated into humans for brain imaging.

We tested a clinically relevant CSF1R inhibitor (BLZ945) in mesothelioma treatment using syngeneic murine models...Combined CSF1R inhibitor with an anti-PDL1 agent was more effective in retarding mesothelioma growth compared to each monotherapy. In experimental mesotheliomas, CSF1R inhibition abrogates tumor progression by limiting suppressive myeloid populations and enhancing CD8+ cell activation and acts synergistically with anti-PDL1.

CSF1R inhibitor BCI-1229 is more potent than the commercially available inhibitor BLZ-945 in the CSF1R-dependent cell line M-NFS-60 (Figure 1B)...Conclusion In summary, we employ a novel approach to develop combined CSF1R/FLT3 targeted therapy for AML to assess the protective tumor microenvironment and by direct leukemic cell death. Ultimately, our goal is to facilitate translational medicine by performing rigorous preclinical experiments and to select compounds to be tested in a clinical trial setting combined with conventional and other novel therapeutics.

In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.

P1/2, N=200, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2021 --> Mar 2022 | Trial primary completion date: Jun 2021 --> Mar 2022

Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. We also detected presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF-1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAFV600E and wild-type forms of the disease.

To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.

P1/2, N=200, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2021 --> Jun 2021 | Trial primary completion date: Mar 2021 --> Jun 2021

Treating E-GBM-derived tumor cells with the BRAF-V600E inhibitor, PLX4032 (vemurafenib), resulted in a dose-dependent reduction in cell viability that was amplified by addition of the CSF-1R inhibitor, BLZ945. The present case provides insight into the cellular nature of E-GBM and introduces several possibilities for effective targeted therapy for these patients.

The multicellular gene network approach developed herein indicates profound roles of the macrophage-mediated tumor microenvironment in the progression and drug resistance of gliomas. The identified macrophage-related gene signature has good prognostic value for predicting resistance to targeted therapeutics and survival of glioma patients, implying that combining current targeted therapies with new macrophage-targeted therapy may be beneficial for the long-term treatment outcomes of glioma patients.

Flow cytometric, soluble ligand and gene expression profiling demonstrated BLZ945-mediated CSF-1R blockade in the periphery and tumor microenvironment in patients with advanced cancers. Ongoing analyses include identification of transcriptomic signatures associated with response. These data support further clinical development of BLZ945 ± spartalizumab in advanced cancers (NCT02829723).

BLZ945 ± spartalizumab showed an acceptable safety pattern; RP2D was declared as 1200 mg (4d on/10d off) for single-agent BLZ945, the MTD was 700 mg (4d on/10d off) for BLZ945 + spartalizumab. Encouraging preliminary antitumor activity was observed in pts with GBM.

P1/2, N=202, Recruiting, Novartis Pharmaceuticals | N=151 --> 202

Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation...Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A)...Clinical trial information: NCT04045613. Research Funding: Basilea Pharmaceutica International Ltd.

Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation...Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A)...Clinical trial information: NCT04045613. Research Funding: Basilea Pharmaceutica International Ltd.

In conclusion, we have shown that PD-L1+ hepatic macrophages, including Kupffer cells, are more potent in facilitating CTL exhaustion and CCA tumor progression than PD-L1+ cancer cells. Moreover, macrophage targeted therapy appears to be a promising therapeutic approach in CCA.