First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors

Oordt, C. Willemien Menke-van der Houven van; Gomez‐Roca, Carlos; Herpen, Carla van; Coveler, Andrew L.; Mahalingam, Devalingam; Verheul, Henk M.W.; Graaf, Winette T.A. van der; Christen, Randolph D.; Rüttinger, Dominik; Weigand, Stefan; Cannarile, Michael A.; Heil, Florian; Brewster, Michael; Walz, Antje-Christine; Nayak, Tapan K.; Guarin, Ernesto; Méresse, Valérie; Tourneau, Christophe Le

doi:10.18632/oncotarget.11098

Cited by 100 publications

(72 citation statements)

References 14 publications

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“…This highlights CD44 as a potential therapeutic target in pancreatic cancer. However, while preclinical studies support this notion , a phase I clinical trial evaluating an antibody interfering with the hyaluronan‐binding domain of CD44 had to be terminated due to lack of clinical response . This trial, however, included 65 patients with 20 different tumour forms and such a liberal inclusion criterion might have obscured clinical responses pertinent to certain cancer forms.…”

Section: Discussionmentioning

confidence: 99%

Novel prognostic markers within the CD44‐stromal ligand network in pancreatic cancer

Franklin

Billing

Öhlund

et al. 2018

The Journal of Pathology CR

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The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44‐stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas‐phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Novel prognostic markers within the CD44‐stromal ligand network in pancreatic cancer

Franklin

Billing

Öhlund

et al. 2018

The Journal of Pathology CR

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“…More recently, RG7356 mAb, which targets the HA binding domain of CD44, was also used in a phase I clinical trial with patients with metastatic or locally advanced CD44-expressing solid malignancies. This mAb showed weak clinical activity, and the study was also terminated [37]. The targeting of total CD44 may interfere with T helper 1 cell antitumor function, which could weaken antitumor immune response [38].…”

Section: Discussionmentioning

confidence: 99%

Impact of Truncated O-glycans in Gastric-Cancer-Associated CD44v9 Detection

Moreira

Pinto

Gomes

et al. 2020

Cells

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CD44 variant isoforms are often upregulated in cancer and associated with increased aggressive tumor phenotypes. The CD44v9 is one of the major protein splice variant isoforms expressed in human gastrointestinal cancer cells. Immunodetection of CD44 isoforms like CD44v9 in tumor tissue is almost exclusively performed by using specific monoclonal antibodies. However, the structural variability conferred by both the alternative splicing and CD44 protein glycosylation is disregarded. In the present work, we have evaluated the role of O-glycosylation using glycoengineered gastric cancer models in the detection of CD44v9 by monoclonal antibodies. We demonstrated, using different technical approaches, that the presence of immature O-glycan structures, such as Tn and STn, enhance CD44v9 protein detection. These findings can have significant implications in clinical applications mainly at the detection and targeting of this cancer-related CD44v9 isoform and highlight the utmost importance of considering glycan structures in cancer biomarker detection and in therapy targeting.

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“…RG7356 is thought to partially act by triggering an inflammatory immune response leading to macrophage recruitment and direct tumor cell killing by antibody-dependent cellular phagocytosis [4]. RG7356 appears to be well tolerated in a phase I dose escalation study in acute myelogenous leukemia (AML) and solid tumors [8]. In contrast, in our paper we described macrophage derived OPN as promoting tumor growth [1], yet these findings are not necessarily contradictory.…”

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confidence: 88%