L19-IL2 Immunocytokine in Combination with the Anti-Syndecan-1 46F2SIP Antibody Format: A New Targeted Treatment Approach in an Ovarian Carcinoma Model.

Paola Orecchia,Barbara Carnemolla,Romana Conte,Gabriella Pietra,Nicolò Bizzarri,Simone Ferrero,Enrica Balza,Maria Cristina Mingari

doi:10.3390/cancers11091232

Paola Orecchia, Barbara Carnemolla + Show 6 more

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https://doi.org/10.3390/cancers11091232

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Epithelial ovarian cancer (EOC) is the fifth most common cancer affecting the female population. At present, different targeted treatment approaches may improve currently employed therapies leading either to the delay of tumor recurrence or to disease stabilization. In this study we show that syndecan-1 (SDC1) and tumor angiogenic-associated B-fibronectin isoform (B-FN) are involved in EOC progression and we describe the prominent role of SDC1 in the vasculogenic mimicry (VM) process. We also investigate a possible employment of L19-IL2, an immunocytokine specific for B-FN, and anti-SDC1 46F2SIP (small immuno protein) antibody in combination therapy in a human ovarian carcinoma model. A tumor growth reduction of 78% was obtained in the 46F2SIP/L19-IL2-treated group compared to the control group. We observed that combined treatment was effective in modulation of epithelial-mesenchymal transition (EMT) markers, loss of stemness properties of tumor cells, and in alleviating hypoxia. These effects correlated with reduction of VM structures in tumors from treated mice. Interestingly, the improved pericyte coverage in vascular structures suggested that combined therapy could be efficacious in induction of vessel normalization. These data could pave the way for a possible use of L19-IL2 combined with 46F2SIP antibody as a novel therapeutic strategy in EOC.

Highlights

Similar to normal organs, tumors need to establish a blood supply to satisfy their demand for oxygen and nutrients, which are prerequisites for tumor growth and progression [1,2,3]
L19-IL2 is an immunocytokine composed of an scFv specific for the angiogenesis-associated B-fibronectin (B-FN) isoform and IL2 selectively accumulated on tumor neovasculature, and showed a good anti-tumor activity in preclinical models and PhaseI/II. Clinical trials, both in solid and hematological tumors [37,38,39,40]. We show that both SDC1 and B-fibronectin isoform (B-FN) are involved in Epithelial ovarian cancer (EOC) progression and we hypothesize a possible employment of L19-IL2 and of the new anti-syndecan-1 46F2 small immunoprotein (46F2SIP) antibody format in combined therapy to treat a human ovarian carcinoma model
When patients were stratified by tumor grade, using the previous statistic test we observed that plasma SDC1 (pSDC1) levels in G1/G2 (p = 0.0158) and G3 (p = 0.0046) patients were significantly different to the control group

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Introduction

Tumors need to establish a blood supply to satisfy their demand for oxygen and nutrients, which are prerequisites for tumor growth and progression [1,2,3]. The resulting tumor blood vessels are structurally and functionally abnormal. They are tortuous, inefficient, and immature, with poor pericyte coverage composed of tumor endothelial cells with loose endothelial junctions [6,7]. These characteristics contribute to a pro-tumorigenic and immunosuppressive environment altering the therapy response of tumor cells [1]. One strategy is to use antiangiogenic therapies in association with chemotherapy or radiotherapy to augment their efficacy by benefiting from the vascular “normalization” induced by antiangiogenic therapy [6,8,9].

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