Phase II trial of Belagenpumatucel-L, a TGF-β2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients

Nemunaitis, John; Nemunaitis, Michael; Senzer, Neil; Snitz, P; Bedell, Cynthia; Kumar, Padmasini; Pappen, Beena O.; Maples, Phillip B.; Shawler, Daniel L.; Fakhrai, Habib

doi:10.1038/cgt.2009.15

Cited by 129 publications

(64 citation statements)

References 32 publications

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“…When injected into the patient, Lucanix promotes an antihost NSCLC cytotoxic T cell response, and vaccine immunogenicity is postulated to be potentiated by reduced TGF-b2 production. Phase I and II trials went well, the drug was found to be safe, and the phase II results suggested some therapeutic benefit (Nemunaitis et al , 2009. However, a phase III trial to examine benefit as a NSCLC maintenance therapy following primary treatment (270 Lucanix-treated vs. 262 placebo-treated NSCLC patients) did not meet its primary endpoint criterion of increased overall survival (OS) (Giaccone et al 2015).…”

Section: Update On Interventional Clinical Oncology Trials With Tgf-bmentioning

confidence: 99%

Targeting TGF-β Signaling for Therapeutic Gain

Akhurst

2017

Cold Spring Harb Perspect Biol

169

139

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Transforming growth factor bs (TGF-bs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-b type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-b ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-b signaling for therapeutic benefit. This review will cover the basics of TGF-b signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-b blockade strategies, and give an update on preclinical and clinical trials for TGF-b blockade in a variety of solid tumor types.

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Section: Update On Interventional Clinical Oncology Trials With Tgf-bmentioning

confidence: 99%

Targeting TGF-β Signaling for Therapeutic Gain

Akhurst

2017

Cold Spring Harb Perspect Biol

169

139

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“…The relevance of TGF-b signaling for disease progression has been particularly recognized in tumors where cancer cells retain the core TGF-b signaling components, as is often the case in breast and lung cancers (Kang et al 2003;Elliott and Blobe 2005;Massague 2008;Padua and Massague 2009). Indeed, in lung adenocarcinoma (ADC), the most common subtype of lung cancer with a high mortality rate, increased TGF-b1 expression correlates with tumor progression and poor patient survival, and various experimental model systems support a prometastatic role for TGF-b in these tumors (Lund et al 1991;Hoffman et al 2000;Hasegawa et al 2001;Gibbons et al 2009;Nemunaitis et al 2009;Toonkel et al 2010;Provencio et al 2011;Vazquez et al 2013). However, a major remaining challenge is the identification of TGF-b target genes that drive the different steps of metastasis, especially since TGF-b modulates gene expression in a highly cell-and context-specific manner (Padua and Massague 2009;Mullen et al 2011;Massague 2012).…”

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confidence: 99%

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis

Tai

Jin

et al. 2015

Genes Dev.

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The mechanisms by which TGF-b promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-b potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-b's prometastatic effects by enhancing tumor cell extravasation. TGF-b-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-b and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-b/Smad pathway that promotes lung ADC cell extravasation and metastasis.

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“…Therefore, TGFß1 expression is an indicator of the aggressiveness or malignancy of solid cancers. Consequently, various molecular targeting therapies for TGFß1 and its receptors are being investigated (20)(21)(22), and some have already been introduced clinically (23)(24)(25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Expression of TGFß1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin

et al. 2011

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Abstract. It has been suggested that expression of TGFß1 and its receptors [TGFß receptor type I (TßRI) and TGFß receptor type II (TßRII)] may play a key role in the proliferation and progression of epithelial ovarian cancer. We investigated the biological significance of TGFß1 and its receptors, as well as their association with the tumor response to paclitaxel (PTX) and carboplatin (CBDCA). We studied 24 patients with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had undergone surgery and chemotherapy with PTX and CBDCA. Tissues from the primary tumor were examined and the expression of TGFß1, TßRI, and TßRII mRNA was assessed by the RNase protection assay. It was found that TGFß1 mRNA expression was significantly lower in the tumors of patients who had optimal surgery than in the tumors of patients with suboptimal surgery. TGFß1 mRNA expression was also significantly lower in tumors with high sensitivity to PTX and CBDCA than in those with low sensitivity. TßRI mRNA expression was not associated with any clinicopathological factors. Expression of TßRII mRNA was significantly higher in clear cell adenocarcinoma and mucinous adenocarcinoma, while it was lower in serous adenocarcinoma and endometrioid adenocarcinoma. Moreover, it tended to be higher in early-stage tumors compared with advanced tumors. Among TGFß1, TßRI, and TßRII, expression of TGFß1 mRNA was most strongly associated with progression-free survival. When the prognosis of the patients with advanced cancer was compared on the basis of TGFß1 mRNA expression, those whose tumors showed low expression tended to have a better prognosis than those whose tumors showed high expression. It is suggested that TGFß1 mRNA expression is an indicator of tumor sensitivity to standard therapy with PTX and CBDCA, that it can identify biologically aggressive and highly malignant tumors and that it can predict the prognosis of patients with ovarian cancer.

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Phase II trial of Belagenpumatucel-L, a TGF-β2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients

Cited by 129 publications

References 32 publications

Targeting TGF-β Signaling for Therapeutic Gain

Targeting TGF-β Signaling for Therapeutic Gain

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis

Expression of TGFß1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin

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