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Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC

ABSTRACT: This is a First-in-Human Phase IA/IB/II open label dose escalation study of intravenous (IV) administration of ONC-392, a humanized anti-CTLA4 IgG1 monoclonal antibody, as single agent and in combination with pembrolizumab in participants with advanced or metastatic solid tumors and non-small cell lung cancers.

DISEASE(S): Sarcomas,Carcinoma,Salivary Gland Cancer,Small Cell Lung Cancer,Metastatic Melanoma,Non Small Cell Lung Cancer,Urothelial Carcinoma,Lung Neoplasms,Metastatic Renal Cell Carcinoma,Ovarian Cancer,Metastatic Head And Neck Carcinoma,Pancreas Cancer,Gastric Cancer,Advanced Solid Tumor,Pancreatic Neoplasms,Salivary Gland Neoplasms,Metastatic Colorectal Cancer,Metastatic Breast Cancer,Cervical Cancer,Small Cell Lung Carcinoma,Carcinoma, Adenoid Cystic,Adenoid Cystic Carcinoma,Metastatic Prostate Cancer,Gastroesophageal Junction Adenocarcinoma,Esophageal Cancer

PROVIDER: 2320193 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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MHC Class Ib-restricted CD8+ T Cells Possess Strong Tumoricidal Activities

Project description:The tumoricidal effects of CD8+T cells are well acknowledged, but how MHC Ib-restricted CD8+T (Ib-CD8+T) cells contribute to anti-tumor immunity remains obscure. Here, we show that infusion of MHC Ia+ cells to Kb-/-Db-/- mice induced the expansion of Ib-CD8+T cells in tumors and potently inhibited tumor progression. Such priming of Ib-CD8+T cells by MHC-Ia is not MHC haplotype restricted and MHC Ia tetramers alone can prime Ib-CD8+T cells for activation. The MHC Ia priming promoted Tbet expression in Ib-CD8+T cells and in absence of Tbet, such priming effect diminished. Importantly, these tumoricidal Ib-CD8+T cells are positive for CX3CR1, and exhibit rapid proliferation, high expression of cytotoxic factors, and prolonged persistence at tumor sites. Adoptive transfer of CX3CR1+Ib-CD8+T cells to wild type mice resulted in potent anti-tumor effects. Our findings unravel an uncharacterized function of MHC Ia molecules in immunoregulation and raise the possibility of using Ib-CD8+T cells in tumor immunotherapy.

2023-10-03 | GSE164271 | GEO

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Project description:Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

2022-01-24 | GSE194166 | GEO

LC7 Proteomic Analysis of Matched Control and NSCLC Lung Adenocarcinoma Tissue.

Project description:Non-small cell lung adenocarcinoma is the most frequently diagnosed lung cancer type and remains the leading cause of cancer mortality for men and women in the United States. Management of lung cancer is hindered by high false-positive rates due to the inability to resolve benign versus malignant tumors. Therefore, better molecular analysis comparing malignant and non-malignant tissues will provide additional evidence of the underlying biology contributing to tumorigenesis. In the current study, we utilized a proteomics approach to analyze 38 malignant and non-malignant paired tissue samples obtained from current or former smokers with early stage (Stage IA/IB) lung adenocarcinoma. Statistical mixed effects modeling and orthogonal partial least squares discriminant analysis were used to identify key cancer-associated perturbations in the malignant tissue proteome. Identified proteins were subsequently assessed against clinicopathological variables.

2016-12-23 | PXD002612 | Pride

mRNA gene expression analysis of 104 early stage non-small cell lung cancers

Project description:104 early-stage (IA and IB) non-small cell lung cancers were evaluated with the Illumina Human HT-12 v4 BeadChip.

2015-06-01 | E-MTAB-3448 | biostudies-arrayexpress

Outcome differences between PD-1/PD-L1 inhibitors-based monotherapy and combination treatments in NSCLC with brain metastases.

Project description:IntroductionWithout the clear immunophenotyping of brain metastases (BrMs), the optimal treatment strategy based on PD-1/PD-L1 inhibitor for patients with non-small-cell lung cancer (NSCLC) and BrMs remains unknown.Methods308 patients with NSCLC received PD-1/PD-L1 inhibitor-based monotherapy or combination therapy were retrospectively identified. Kaplan-Meier curves with log-rank tests were used to determine the treatment outcomes differences. Transcriptomic analysis of paired primary lung lesions and BrMs were performed to dissect the specific tumor immune microenvironment (TIME) of BrMs.ResultsThe presence of BrMs was associated with significantly inferior PFS (2.5 vs. 3.7 months; P = 0.0053) and OS (8.3 vs. 15.4 months; P = 0.0122) in monotherapy group, while it was only associated with poorer PFS (4.6 vs. 7.0 months; P = 0.0009) but similar OS (22.8 vs. 21.0 months; P = 0.9808) in combination treatment group. Of patients with BrMs, PD-1/PD-L1 inhibitor plus antiangiogenic therapy was associated with longest PFS (7.7 vs. 3.2 vs. 2.5 months; P = 0.0251) and OS (29.2 vs. 15.8 vs. 8.3 months; P = 0.0001) when compared with PD-1/PD-L1 inhibitor plus chemotherapy or anti-PD-1/PD-L1 monotherapy. Multivariate analyses suggested that combination treatment was independently correlated with significantly longer PFS (P = 0.028) and OS (P < 0.001) in patients with BrMs. Transcriptomic analysis showed a suppressive TIME in BrMs with decreased CD4+ T cells and M1 macrophages but increased M2 macrophages infiltration.ConclusionNSCLC with BrMs obtained barely satisfactory overall benefit from anti-PD-1/PD-L1 monotherapy, partly due to its immunosuppressive TIME. PD-1/PD-L1 inhibitor-based combination treatment, especially anti-PD-1/PD-L1 plus anti-angiogenic treatment, could significantly improve the clinical outcomes of patients with NSCLC and BrMs.

| S-EPMC10288673 | biostudies-literature

Proprioception is governed by highly diverse and versatile sensory neuron types

Project description:Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with advanced virus- and genetic tracings, we have molecularly identified the 3 main types of PNs (Ia, Ib and II) and unexpectedly found that they segregate into 8 subgroups. Our data further reveal a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles, that together contribute to the sensory monitoring of complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later along with increased motor activity and show versatility in the adult following exercise training, suggesting adaptive proprioceptive function.

2020-12-25 | GSE156180 | GEO

The expression profiles of exosomal miRNAs associated with response to anti-PD-1/PD-L1 monotherapy in advanced NSCLC patients.

Project description:Exosomal miRNAs involved in response to anti-PD-1/PD-L1 monotherapy in advanced NSCLC patients were successfully identified through the microoarray analysis.

2023-01-12 | GSE189045 | GEO

LC7 Proteomic Analysis of Matched Control and NSCLC Lung Adenocarcinoma Tissue.

2017-03-31 | MSV000080825 | MassIVE

Gastric Cancer Gene Expression Profiling

Project description:This series studied the patterns of gene expression among different types of gastric tumors. Gastric tumors and adjacent non-tumor normal tissues were obtained from 50 gastric cancer patients of diverse stages (IA, IB, II, IIIA, IIIB, and IV), tumor types (intestinal, diffuse, or mixed), and degree of tumor differentiation (moderately or poorly differentiated). Keywords: Cancer patient samples

2006-06-01 | GSE3438 | GEO

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

Project description:AimCombined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen.MethodsER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen.ResultsThe in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (?) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (?5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research.ConclusionThe experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

| S-EPMC4933764 | biostudies-literature

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