P2, N=36, Recruiting, Deciphera Pharmaceuticals, LLC | Not yet recruiting --> Recruiting

Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic.

P2, N=36, Not yet recruiting, Deciphera Pharmaceuticals, LLC

P2, N=21, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Recruiting --> Active, not recruiting | Trial completion date: Nov 2026 --> May 2026

Inhibition of microglia by pretreatment with minocycline or depletion of microglia by PLX3397 abolished the preventive effect of low-dose LPS pre-injection on mSPS-induced anxiety- and fear-like behavior and neuroinflammatory responses. These results suggest that pre-stimulation of microglia may prevent the development of PTSD-like behaviors by attenuating the development of neuroinflammatory responses. This could help to develop new strategies to prevent the damaging effects of harmful stress on the brain.

To manipulate microglia, we used low-dose treatment with a highly selective CSF1R inhibitor called PLX5622 (PLX)...Across treatment groups, MRI-detected anatomical volumes at P19 and P63 were associated with microglia and proliferating microglia densities, respectively. Overall, our study demonstrates that low-dose PLX treatment produces a sex-dependent response in juvenile mice, that manipulation of microglia alters CRT-induced volume changes and that microglia density and MRI-derived volume changes are correlated in this model.

In conclusion, targeting FLT3 as a receptor tyrosine kinase with PLX3397 represents a promising therapeutic strategy for improving outcomes in patients with FLT3-mutated AML. Further clinical investigations are warranted to validate the efficacy and safety of PLX3397 and to optimize treatment strategies for AML patients based on the FLT3 mutational status.

Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model...Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.

The results of our study showed that blocking microglial activation via CSF1R may help prevent cancer-induced orofacial pain.

RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.

Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

These results imply that the replacement of microglia in the aged brain may alleviate brain damage and neuroinflammation, and therefore, ischemic brain damage. Thus, targeting microglia could be a promising therapeutic strategy for ischemic stroke.

P1/2, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial completion date: Jun 2024 --> Aug 2028 | Trial primary completion date: Dec 2023 --> Jul 2026

We demonstrate that TREM2 has the potential to alleviate WMI following TBI, possibly through the DHCR24/LXR pathway in microglia.

P1, N=32, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Phase classification: P1b --> P1 | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P3, N=40, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Trial completion date: Mar 2024 --> Feb 2026

P=N/A, N=6, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Phase classification: P1/2 --> P=N/A | Trial completion date: Mar 2024 --> Mar 2025

P3, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial primary completion date: Mar 2024 --> Aug 2023

Oxygen-glucose deprivation causes an increase in NR4A1 mRNA in astrocytes as well as its nuclear to cytoplasmic transfer. Furthermore, reoxygenation enhances NR4A1 transcription and promotes its nuclear translocation.

P1/2, N=43, Active, not recruiting, Gulam Manji | Recruiting --> Active, not recruiting | Phase classification: P2 --> P1/2 | Trial completion date: Mar 2024 --> Jun 2024

RNA-seq further confirms the enhanced immune cell function. Consequently, P@ZIF/M1-KTP has great potential as a novel adoptive cellular therapeutic strategy for tumors.

In vivo, PXB17 significantly halted CRC growth, with a stronger effect than PLX3397. In particular, PXB17 potently enhanced therapeutic activity of PD-1 mAb in CT-26 (MSS) model and prevented tumor recurrence in MC-38 (MSI-H) model by promoting formation of long-term memory immunity. Our study opens a new avenue for CSF1R in tumor innate and adaptive anti-tumor immunomodulatory activity and suggests that PXB17 is a promising immunotherapy molecule for enhancing the efficacy of PD-1 mAb or reducing tumor recurrence of CRC.

Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

The results of immunoblotting assays suggested that silybinin as well as compound glycyrrhizin inhibited the protein expression of CYP3A4 and CYP2C9 in rats. Therefore, the combination of pexidartinib with silybinin and compound glycyrrhizin should be monitored to avoid clinical adverse effects.

Our method allowed us to study the influence of three different factors-dexamethasone, PLX5622, and CXCL2-in a well-controlled, simplified, and straight-forward mechanistic manner, and at the same time in a more realistic ex vivo scenario compared to in vitro studies. In our model, we showed a GBM outgrowth enhancing synergism between CXCR2-blocking and Dex-treatment in the native condition, which was levelled by PLX5622-pretreatment.

Combination treatment also induced favorable systemic antitumor immunity in the spleen and lymph node. In conclusion, our findings provide insights into the synergy between mDex-based immunotherapy and PLX-3397 as the combination overcame the disadvantages associated with monotherapy and offer a therapeutic strategy for the treatment of solid tumors including melanoma.

Their temporal alteration suggests an association with tumor recurrence after BNCT, making M-MDSCs a potential intervention target. Our preliminary results showed that PLX-3397 had strong M-MDSCs, TAMs, and TIL (tumor-infiltrating lymphocyte) modulating effects that could synergize tumor control when combined with BNCT.

P1/2, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2022 --> Dec 2023

P1, N=54, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.

The cell membrane-derived nanoparticles (CMNPs) deriving from the MiaPaCa-2 cells (MPC2-CMNPs) were loaded with the chemotherapeutic drug paclitaxel (PTX), and the CMNPs deriving from M2-polarized macrophages (M2-CMNPs) were loaded with the colony-stimulating factor 1 receptor inhibitor, pexidartinib (PXDB). Finally, we evaluated the PTX and PXDB-loaded CMNPs' effect on the viability of all the used TME cell lines alone or in combination. Overall, this pilot study showed the potential of the CMNPs to cross an in vitro stroma model and act synergistically to treat PDAC.

In the current study, the metabolic activation of PEX was investigated in human/mouse liver microsomes (HLM/MLM) and primary human hepatocytes (PHH) using glutathione (GSH) and methoxyamine (NHOMe) as trapping reagents. CYP3A4 and CYP3A5 were identified as the primary enzymes responsible for the formation of these adducts using recombinant human P450s and CYP3A chemical inhibitor ketoconazole. Overall, our studies suggested that PEX metabolism can produce reactive metabolites mediated by CYP3A, and the association of the reactive metabolites with PEX hepatotoxicity needs to be further studied.

In Part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Pts with TGCT not amenable to surgery and no prior anti-CSF1/CSF1R therapy (previous treatment with imatinib or nilotinib was allowed) were enrolled and treated with vimseltinib 30 mg twice weekly (recommended phase 2 dose). Longer follow-up demonstrated that vimseltinib continued to be well tolerated with a manageable safety profile in pts with TGCT not amenable to surgery with no prior anti-CSF1/CSF1R therapy. Antitumor activity continued to improve with a promising overall ORR. At week 25, the majority of responders experienced ≥30% reductions in worst and average pain.

In two preclinical mouse models of MPNST, we combined the oncolytic virus T-VEC with myeloid-cell targeting therapeutics, Pexidartinib or Trabectedin, to assess the combination therapy's antitumor efficacy and survival benefits. Our findings provide compelling evidence that myelomodulatory therapies can augment the antitumor T-cell response and improve the therapeutic benefits of oncolytic virotherapy in murine models of MPNST. These results provide valuable insights for designing and implementing future immunotherapeutic strategies in the management of MPNST.

Pts with TGCT not amenable to surgery who received prior anti-CSF1/CSF1R therapy (including pexidartinib, cabiralizumab, or vimseltinib) were enrolled and treated with vimseltinib 30 mg twice weekly (recommended phase 2 dose). Longer follow-up demonstrated that vimseltinib continued to be well tolerated with a manageable safety profile in pts with TGCT not amenable to surgery who received prior anti-CSF1/CSF1R therapy. Antitumor activity continued to improve in this pretreated population, with an increased ORR. At week 25, all responders experienced ≥30% reductions in worst and average pain.

In Asian patients with symptomatic TGCT not amenable to improvement with surgery, pexidartinib demonstrated clinical benefit in tumor response and improvement in joint function. The overall safety profile of pexidartinib was comparable with previous data. Hepatotoxicity was manageable with frequent liver test monitoring and dose modifications as defined in the protocol, and no new safety signals were observed in this Asian population.

To assess the mechanism of CSF-1-mediated suppression of immunotherapy, Isolated PBMC, activated with phytohemagglutinin (PHA) with or without pembrolizumab (20 nM), were cultured alone, or in the presence of macrophages or on an established NSCLC monolayer...The use of Pexidartinib (PLX-3397), a CSF-1R inhibitor, reversed the effects of CSF-1 by restoring lymphocyte activation. However, these effects were dependent on the presence of monocytes/macrophages, suggesting that the immune suppression mediated by CSF-1 was an indirect effect resulting from the stimulation of monocytes that promote their differentiation into macrophages. Conclusions Our study suggests that plasma levels of CSF-1 could serve as a useful predictive biomarker for resistance to ICIs, while targeting the CSF-1/CSF-1R signaling pathway could potentially overcome resistance to ICIs in patients with NSCLC.

Astrocyte - Glutamatergic neuron circuit of DRN participate in the regulation of visceral pain induced by pancreatic cancer in mice, which provides new insights for the discovery of effective targets for the treatment of pancreatic cancer visceral pain.