Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma

Riechelmann, Herbert; Sauter, Alexander; Golze, Wolfram; Hanft, Gertraud; Schroen, Carsten; Hoermann, Karl; Erhardt, Thomas; Gronau, Silke

doi:10.1016/j.oraloncology.2007.10.009

Cited by 170 publications

(125 citation statements)

References 14 publications

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“…Although the phase I clinical trials appeared to be promising, 1 patient developed toxic epidermal necrolysis and succumbed to the disease. For this reason, the development of this drug has been terminated (27). Despite the termination of the trials, CD44v6 remains a valid target for anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

et al. 2011

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Abstract. CD44v6 has been causally associated with the development of metastases and with poor prognosis in various human malignancies. To elucidate the clinicopathological significance of CD44v6 expression in esophageal squamous cell carcinoma (ESCC), the present study aimed to investigate the expression of CD44v6 using immunohistological techniques. Using specific antibodies against CD44v6 and CD44s, expression of the proteins was analyzed immunohistochemically in 63 primary esophageal ESCCs, which were previously resected at the Nagoya City University Hospital without pre-operative induction therapy. Using light microscopy, the positive expression of CD44v6 was divided into a low-or highexpression group. The expression of CD44v6 in ESCC was analyzed with respect to various clinicopathological characteristics. The frequency of CD44v6 expression was 90.5% (57/63). The CD44v6 high-expression group comprised 55.6% of the patients (n=35) and the low expression group included 44.4% of the patients (n=28). In this study, no significant difference was observed between any clinicopathological factor and the immunohistochemical expression of CD44v6. In patients with high levels of CD44v6 expression, survival was markedly worse (p=0.0327). Favorable outcomes were observed for the clinicopathological characteristics of 6 patients whose tissue immunohistochemical expression of CD44v6 was not detected. Moreover, multivariate analysis confirmed that expression of CD44v6 was an independent prognostic indicator (risk ratio =2.793; p=0.0301). Overexpression of CD44v6 is a useful prognostic indicator of ESCC. Therefore, CD44v6 should be investigated as a potential target for therapy.

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Section: Discussionmentioning

confidence: 99%

Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

et al. 2011

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“…The main limiting toxicity of the CD44v6 MAb immunoconjugates with Mertansine in Phase I clinical studies was severe skin reactions due to abundant 'off-target' expression of the CD44v6 antigen in normal squamous cells [5]. Fatal complications of CD44v6-MAb-Mertansineadministration, such as toxic epidermal necrolysis, caused early termination of clinical development of these MAbs [4,5] On the other hand, a drug delivery approach based on the HA--CD44 axis, wherein Irinotecan was enveloped non-covalently within a domain of~750 kDa HA, successfully passed Phase I toxicity assessments [6], which led to further clinical studies to investigate the utility of this axis.…”

Section: Clinical Studies Assessing Cd44-targeted Drug Delivery and Rmentioning

confidence: 99%

“…Fatal complications of CD44v6-MAb-Mertansineadministration, such as toxic epidermal necrolysis, caused early termination of clinical development of these MAbs [4,5] On the other hand, a drug delivery approach based on the HA--CD44 axis, wherein Irinotecan was enveloped non-covalently within a domain of~750 kDa HA, successfully passed Phase I toxicity assessments [6], which led to further clinical studies to investigate the utility of this axis. A Phase II study from Australia demonstrated improved progression-free survival (PFS) in metastatic colorectal cancer (CRC) patients treated with HA--Irinotecan compared to the arm with free Irinotecan (5.2 vs 2.4 months, respectively; p = 0.007), and thus warranted an expanded, multicenter Phase III study [7].…”

Section: Clinical Studies Assessing Cd44-targeted Drug Delivery and Rmentioning

confidence: 99%

CD44 as a drug delivery target in human cancers: where are we now?

Şahin

Klostergaard²

2015

Expert Opinion on Therapeutic Targets

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“…For example, various studies have suggested potential prognostic values for p53 mutations, enhanced expression of epidermal growth factor (EGFR), transforming growth factor-α (TGF-α) or cyclin D1 (4-6). More recently, novel CD44v6 targeting humanized antibodies were coupled with toxic substances in order to improve response rates in HNSCC (7,8).…”

Section: Introductionmentioning

confidence: 99%

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

et al. 2012

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Abstract. Head and neck squamous cell carcinoma (HNSCC)is an aggressive epithelial malignancy. It is known to be the most common neoplasm appearing in the upper aerodigestive tract. The poor 5-year survival rate has remained unchanged in the last decades even though improved techniques in surgery, radiation and chemotherapy have been established. In contrast to the overall decreasing incidence of head and neck cancer in the US, the incidence of HPV-associated oropharyngeal cancer is increasing, indicating the importance of viral etiology. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). Matrix metalloproteinases (MMP) have been shown to play key roles in the remodeling of the ECM. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. But it also has an inhibitory impact, e.g., on the protein-tyrosine-kinase (PTK) receptor c-kit and on its PTK activity in HNSCC. In this study, we incubated the HNSCC cell lines HNSCC 11A and 14C and the p16-positive SCC line CERV196 with increasing concentrations of imatinib or carboplatin. After an incubation time of up to 10 days, we evaluated MMP-2 and -14 expression by ELISA techniques and immunohistochemistry. MMP-2 and -14 expression was demonstrated in all incubated tumor cell lines. Especially incubation with imatinib resulted in a significant decrease in MMP expression in incubated cell lines. Our results indicate that the expression of MMP-2 and -14 is suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially keeping in mind the moderate toxicity of imatinib.

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Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma

Cited by 170 publications

References 14 publications

Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

CD44 as a drug delivery target in human cancers: where are we now?

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

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