211 |
Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel BiomarkerBerszin, Michael, Michaelides, Ioannis, Siemert, Julia, Röhl, Louisa, Wellhausen, Jana, Wald, Theresa, Bohr, Christopher, Künzel, Julian, Gradistanac, Tanja, Dietz, Andreas, Zebralla, Veit, Pirlich, Markus, Wiegand, Susanne, Wichmann, Gunnar 05 April 2023 (has links)
Background: Pembrolizumab and cetuximab are antibodies under investigation in head
and neck squamous cell carcinoma (HNSCC) either as single agents or combined with
cisplatin and other chemotherapeutic drugs, e.g., 5-fluorouracil and/or docetaxel.
However, also the combination of both antibodies may have potential in recurrent/
metastatic (R/M) HNSCC, in particular in cisplatin-resistant or -refractory cases or
patients with comorbid disease, e.g. patients with impaired renal function.
Methods: To clarify potential benefit that may result from such combination, we used the
FLAVINO assay, a short-time ex vivo assay to compare responsiveness of HNSCC to
pembrolizumab, cetuximab and both combined regarding colony formation of epithelial
cells of biopsy-derived tumor samples and their cytokine production within three days
either without or with stimulation with 10 ng/mL interferon gamma (IFN-g). Vascular
endothelial growth factor A (VEGF), monocyte chemoattractant protein 1 (MCP-1 or
CCL2), interleukin 6 (IL-6), IL-8, IFN-g, and interferon gamma-induced protein 10 (IP-10 or
CXCL10) in supernatants were measured by ELISA.
Results: We detected huge heterogeneity in response to cetuximab, pembrolizumab and
both combined with and without IFN-g stimulation. Moreover, we detected a link between
IFN-g induced IP-10 release and improved outcome in those HNSCC patients who were
capable to respond to IFN-g and pembrolizumab, cetuximab and both combined with a
further increase in IP-10 production. We derived an “IP-10 score” that independent from
clinical characteristics of HNSCC patients and therapy regimens applied was able to
predict their outcome.
Conclusions: The heterogeneity in the ex vivo response of cetuximab, pembrolizumab
and both combined with and without IFN-g stimulation identifies subgroups of HNSCC
patients with deviating OS.
|
212 |
The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivoBurns, C.J., Fantino, E., Powell, A.K., Shnyder, Steven, Cooper, Patricia A., Nelson, S., Christophi, C., Malcontenti-Wilson, C., Dubljevic, V., Harte, M.F., Joffe, M., Phillips, I.D., Segal, D., Wilks, A.F., Smith, G.D. January 2011 (has links)
No / The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2- yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639-4642, 2009; Mol Cancer Ther 8:3036-3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC(50) 3.7 +/- 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.
|
Page generated in 0.226 seconds