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Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin)

ABSTRACT: Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin)

PROVIDER: PRJNA773260 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16520006.fastq.gz	Fastqsanger.gz
	SRR16520007.fastq.gz	Fastqsanger.gz
	SRR16520008.fastq.gz	Fastqsanger.gz
	SRR16520009.fastq.gz	Fastqsanger.gz
	SRR16520010.fastq.gz	Fastqsanger.gz

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Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin)

Project description:drugs targeting mitosis might affect the tumor microenvironment and sensitize cancer cells to immunotherapy. BAL101553 monotherapy increased survival in immune checkpoint blockade–resistant SB28 glioblastoma tumors and synergized with anti-CD40 antibody

2021-10-23 | GSE186302 | GEO

Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin).

Project description:Glioblastoma is a highly malignant brain tumor with no curative treatment options, and immune checkpoint blockade has not yet shown major impact. We hypothesized that drugs targeting mitosis might affect the tumor microenvironment and sensitize cancer cells to immunotherapy. We used 2 glioblastoma mouse models with different immunogenicity profiles, GL261 and SB28, to test the efficacy of antineoplastic and immunotherapy combinations. The spindle assembly checkpoint activator BAL101553 (lisavanbulin), agonistic anti-CD40 antibody, and double immune checkpoint blockade (anti-programmed cell death 1 and anti-cytotoxic T lymphocyte-associated protein 4; anti-PD-1 and anti-CTLA-4) were evaluated individually or in combination for treating orthotopic GL261 and SB28 tumors. Genomic and immunological analyses were used to predict and interpret therapy responsiveness. BAL101553 monotherapy increased survival in immune checkpoint blockade-resistant SB28 glioblastoma tumors and synergized with anti-CD40 antibody, in a T cell-independent manner. In contrast, the more immunogenic and highly mutated GL261 model responded best to anti-PD-1 and anti-CTLA-4 therapy and more modestly to BAL101553 and anti-CD40 combination. Our results show that BAL101553 is a promising therapeutic agent for glioblastoma and could synergize with innate immune stimulation. Overall, these data strongly support immune profiling of glioblastoma patients and preclinical testing of combination therapies with appropriate models for particular patient groups.

| S-EPMC8492343 | biostudies-literature

scRNAseq of CD45+ cells within PDAC tumors treateted with CD40/ICB

Project description:Goal: determine how transcriptome of immune cells within the tumor microenvironment changes as a function of CD40 agonist and/or immune checkpoint blockade (anti-PD-1 AND anti-CTLA-4; "ICB") therapy

2020-05-10 | GSE150176 | GEO

Project description:Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin)

| PRJNA773599 | ENA

scRNAseq of CD45+ cells within PDAC tumors treateted with CD40/ICB

Project description:scRNAseq of CD45+ cells within PDAC tumors treateted with CD40/ICB

| PRJNA631402 | ENA

Immunologic and clinical activity to ICB combinations in DAPPER Leiomyosarcoma cohort

Project description:Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients.

2024-01-01 | E-MTAB-12922 | biostudies-arrayexpress

Targeting CD11b+ regulatory B cells via RAS/RAF/PI3K pathway inhibition augments response to immune checkpoint blockade or CD40 agonism in metastatic melanoma

Project description:Abstract Development of effective second-line treatment options for immune checkpoint blockade (ICB) resistant patients with BRAFWTNRASWT or BRAFWTNRASmut melanoma is crucial. While systemic delivery of agonist CD40 (aCD40) plus anti-PD1 (αPD1) showed activity in patients with ICB-resistant melanoma, the objective response rate was modest (15%), in part due to induction of B regulatory cells (Bregs) which suppress CD8+ effector T cells. We previously reported that RAS/RAF/PI3K-inhibition elevated CD40 expression in melanoma cells and sensitized tumors to ICB. Here, we show that treatment of ICB-resistant BRAFWTNRASWT and BRAFWTNRASmut melanoma tumors with the combination of rigosertib (RGS), a RAS/PI3K/AKT-pathway inhibitor, and/or trametinib (T), a MEK1/2 inhibitor, plus aCD40 overcomes ICB resistance. Overexpression of CD40 in melanoma cells effectively reverses ICB-resistance and induces tumor regression upon aCD40+αPD1 treatment. Mechanistically, RGS+T suppressed aCD40-associated CD11b+PD-L1+ B regulatory cells (B11regs), which promoted CD8+ T-cell killing in melanoma. scRNA-Seq analyses confirmed CD40-associated B11regs across cancer types in patients. Statement of Significance Addition of aCD40 treatment to PD1 fails to overcome ICB resistance due to aCD40-induction of B11regs and low expression of CD40 in melanoma cells. Our data demonstrate that addition of RAS/RAF/PI3K inhibitors to aCD40 resolves these issues and provides alternative therapeutic options for ICB-resistant BRAFWTNRASWT or BRAFWTNRASmut metastatic melanoma.

2025-10-23 | GSE291447 | GEO

Rigosertib, a potential RAS-targeted agent, induces CD40 expression on melanoma cells to enhance response to immune checkpoint inhibitors

Project description:Immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma. However, ICB fails in many patients and has dangerous side effects. Rigosertib (RGS), a non-ATP-competitive small molecule RAS mimetic, has the potential to block oncogenic RAS-RAF-MEK-ERK and/or PI3K-AKT-mTOR signaling pathways. RGS treatment (300mg/kg) of melanoma tumor-bearing mice is well tolerated and results in ~50% inhibition of tumor growth as monotherapy and ~70% inhibition in combination with ICB. RGS-induced tumor inhibition depends on the induction of CD40 expression on melanoma cells, followed by immunogenic cell death, leading to an inflamed tumor microenvironment with enrichment of dendritic cells and activated CD8+ T cells. Highlights • RGS impairs melanoma tumor growth via direct killing and immunogenic cell death that promotes an inflamed tumor microenvironment. • RGS-induced tumor inhibition depends on the induction of CD40 expression on melanoma cells. • Combining RGS with αPD1+αCTLA4 improves tumor response. • Tumor CD40 levels are prognostic for therapeutic response to RGS and BRAF inhibitor. Significance: A high CD40 expression level correlates with CD80, ICOS-L, beneficial type I T cell responses, and better survival in melanoma patients (cBioPortal database). Tumor CD40 levels are prognostic for therapeutic response to RGS and BRAF inhibitor (DepMap and Oncomine databases), and RGS induces CD40 expression in melanoma tumor cells. Our preclinical data support the therapeutic use of RGS plus αPD1+αCTLA4 in RAS/RAF/MEK and/or PI3K pathway-activated melanoma tumors and point to the need for clinical trials to determine the clinical benefit of RGS plus ICB for metastatic melanoma patients who do not respond to ICB alone.

2021-06-15 | GSE149737 | GEO

Canonical Hedgehog Signaling Controls Astral Microtubules and Mitotic Spindle Orientation in Neural Progenitors and iPSCs

Project description:Mitotic spindle orientation is crucial for cell fate determination and tissue organization. Although the intracellular machinery governing spindle orientation is well characterized, whether and how secreted factors, such as morphogens, regulate this process remains poorly understood. This study investigated the role of Hedgehog (HH) signaling in modulating mitotic spindle orientation in neural progenitor cells and in induced pluripotent stem cells (iPSCs). Time-lapse microscopy of cerebral organoids and iPSCs revealed that HH signaling increases the angle of the mitotic spindle relative to the apical surface, prolongs mitosis, and enhances spindle rotation. Mechanistically, HH signaling reduces both the number and the length of astral microtubules, key regulators of spindle orientation. This reduction correlates with increased spindle angle in iPSCs. Furthermore, we show that canonical HH signaling, involving GLI-dependent transcriptional regulation, contributes to these effects. RNA sequencing and gene set enrichment analysis (GSEA) revealed that HH signaling upregulates genes associated with microtubule depolymerization, suggesting a transcriptional mechanism by which HH signaling influences astral microtubule dynamics and, consequently, mitotic spindle orientation. These findings highlight a novel link between a morphogen, transcriptional regulation, and the control of mitotic spindle orientation, with implications for development and tissue homeostasis.

2025-06-25 | GSE296672 | GEO

Escherichia coli strain:ICB-10E

Project description:Escherichia coli ICB-10E

| PRJNA292926 | ENA