Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1<sup>+</sup>triple negative breast cancer cells

Mohan, Nishant; Hosain, Salman B.; Zhao, Jun; Shen, Yi; Luo, Xiao; Jiang, Jiangsong; Endo, Yuichi; Wu, Wen Jin

doi:10.1080/2162402x.2019.1624128

Cited by 39 publications

(40 citation statements)

References 39 publications

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“…This study is planned over four distinct phases aiming at: identifying the maximum tolerated dose (MTD) of BDC-1001 as monotherapy (phase 1) or combined with the PD-1 blocker pembrolizumab (phase 2), and testing preliminary efficacy of BD-1001 as standalone intervention (phase 3) or in combination with pembrolizumab (phase 4). The Phase I/IIa dose-escalation clinical trial NCT04101357 is assessing the efficacy, pharmacodynamics, pharmacokinetics and safety of BNT411, a novel TLR7 agonist, either given as a monotherapy in individuals affected by advanced solid tumors or administered in combination with the PD-L1-targeted ICB atezolizumab, 3,[117][118][119] carboplatin and etoposide 120,121 in patients with chemotherapy-naïve extensive-stage small cell lung cancer (ES-SCLC). The synthetic TLR7 agonist DSP-0509 is being investigated for pharmacokinetic profile, tolerability, and safety upon intravenous administration as monotherapy or combined with pembrolizumab, [122][123][124] in adults with advanced solid malignancies (NCT03416335).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Frega

Naour

et al. 2020

OncoImmunology

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Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents.

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Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Frega

Naour

et al. 2020

OncoImmunology

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“…This durable and stable upregulation is facilitated by the histone acetylation of the PD-L1 and PD-L2 genes and was observed in vitro and in vivo in different solid tumor models [85,86]. Tumor-bearing mice receiving class I HDACi combined with PD-1 blockade exhibited a significant reduction in tumor growth and a better overall survival compared to mice receiving single agents [85][86][87][88] (Table 5). In vivo: Murine renal cell carcinoma (RENCA) luciferase-expressing cells implanted in BALB/c mice.…”

Section: Selective Histone Deacetylase Inhibitorsmentioning

confidence: 88%

Immunological Effects of Epigenetic Modifiers

Bezu

Chuang

Liu

et al. 2019

Cancers

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Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.Epigenetic alterations compose a natural and fundamental regulatory system of the genetic information contained in the DNA sequence of normal cells. This program is essential for terminal differentiation processes as well as for the maintenance of homeostasis. Epigenetic modifications occur physiologically at several levels and play a regulatory role in various cellular functions such as transcription, RNA splicing, and nuclear export as well as translation. Three mechanisms are considered to induce epigenetic changes, namely DNA methylation, histone modification, and non-coding RNA-associated gene silencing. DNA methylation occurs in healthy cells via the addition of methyl groups by DNA methyltransferases (DNMT1, DNMT2, DNMT3) on position 5 of cytosine residues at CpG-rich promoter regions in order to silence specific genes (in the case of parental genomic imprinting, repeated, or deleterious genes) [5,6]. Post-translational modifications of histones including methylation, acetylation, phosphorylation, and ubiquitination also impact on the accessibility of chromatin and on transcription [7,8] (Figure 1).Cancers 2019, 11, x 2 of 22 occur physiologically at several levels and play a regulatory role in various cellular functions such as transcription, RNA splicing, and nuclear export as well as translation. Three mechanisms are considered to induce epigenetic changes, namely DNA methylation, histone modification, and noncoding RNA-associated gene silencing. DNA methylation occurs in healthy cells via the addition of methyl groups by DNA methyltransferases (DNMT1, DNMT2, DNMT3) on position 5 of cytosine residues at CpG-rich promoter regions in order to silence specific genes (in the case of parental genomic imprinting, repeated, or deleterious genes). [5,6] Post-translational modifications of histones including methylation, acetylation, phosphorylation, and ubiquitination also impact on the a...

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“…The NCT02298153 ECHO-11O Phase Ib trial evaluated the efficacy, tolerability and safety of the epacadostat administered together with the PD-L1 blocker atezolizumab, [129][130][131] to 29 patients with stage IIIB/IV NSCLC previously treated with platinum derivatives [132][133][134][135][136] chemotherapy in conjunction with a folic acid analogue. [137][138][139] Seventy-nine percent of enrolled patients experienced TRAEs, 17% discontinued treatment due to such effects, one patient showed anticancer partial response, and the maximum tolerated dose (MTD) was not achieved.…”

Section: Published Clinical Trialsmentioning

confidence: 99%

Trial watch: IDO inhibitors in cancer therapy

et al. 2020

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Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", which converts the essential amino acid L-tryptophan (Trp) into the immunosuppressive metabolite L-kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives. In animal tumor models, genetic or pharmacological IDO1 inhibition can cause the (re)activation of anticancer immune responses. Similarly, neoplasms expressing high levels of IDO1 may elude anticancer immunosurveillance. Therefore, IDO1 inhibitors represent promising therapeutic candidates for cancer therapy, and some of them have already entered clinical evaluation. Here, we summarize preclinical and clinical studies testing IDO1-targeting interventions for oncologic indications.

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Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1⁺triple negative breast cancer cells

Abstract: (2019) Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1 + triple negative breast cancer cells, OncoImmunology, 8:9, e1624128,

Cited by 39 publications

References 39 publications

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Immunological Effects of Epigenetic Modifiers

Trial watch: IDO inhibitors in cancer therapy

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Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1+triple negative breast cancer cells

Abstract: (2019) Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1 + triple negative breast cancer cells, OncoImmunology, 8:9, e1624128,

Cited by 39 publications

References 39 publications

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Immunological Effects of Epigenetic Modifiers

Trial watch: IDO inhibitors in cancer therapy

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Product

Resources

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Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1⁺triple negative breast cancer cells