Abstract 4824: Targeting CD30 as a novel treatment strategy in <i>RANBP2-ALK</i>-rearranged inflammatory myofibroblastic tumor
Authors: Ashleigh M. Fordham, James Blackburn, Erin E. Heyer, Jinhan Xie, Emily V. Mould, Andrew J. Gifford, Lisa T. Morgan, Carol Wadham, Mitali Fadia, Jamie I. Fletcher, Karen L. MacKenzie, Toby N. Trahair
Journal: Cancer Research (2019)

Abstract Rationale: Inflammatory myofibroblastic tumors (IMTs) are a particularly rare type of soft tissue sarcoma comprised of myofibroblastic spindle cells and an accompanying inflammatory infiltrate. There is an unmet clinical need for effective treatment regimens for patients diagnosed with IMT with anaplastic lymphoma kinase (ALK) rearrangement, who relapse following ALK inhibitor (ALKi) therapy or who present with aggressive disease. Fusion of RAN Binding Protein 2 (RANBP2) with ALK in IMT is associated with aggressive disease and has been correlated with tumor cell expression of CD30. This study investigated CD30 as a potential therapeutic target in IMT and the efficacy of the CD30-targeted antibody-monomethyl auristatin E conjugate, Brentuximab Vedotin (BV). Methods and Results: In a cohort of five recent IMT patients at the Sydney Children’s Hospital, RANBP2-ALK fusion was identified in three patients (IMT1, IMT2 and IMT3) by RNA capture sequencing, while patients IMT4 and IMT5 (who did not relapse) harbored CLTC-ALK or SEC31A-ALK fusions respectively. Expression of CD30 was confirmed two of three RANBP2-ALK fusion positive tumors by immunohistochemistry. We established cell cultures and xenografts from malignant ascites of IMT1, at diagnosis (IMT1A) and at relapse (IMT1D) after treatment with ALKi’s and low dose chemotherapy. CD30 expression was retained in the cell cultures and xenograft tumors, as demonstrated by flow cytometry and tumor histology. BV was investigated as a potential treatment for IMT with RANBP2-ALK fusion. BV reduced IMT1A and IMT1D cell viability in vitro in resazurin cell viability assays. IMT1A and IMT1D xenograft mice had a partial response to BV which significantly (p&amp;lt;0.0001) prolonged survival compared to untreated controls. However, tumors eventually recurred. Resistance to BV correlated with upregulation of P-glycoprotein and reduced CD30 antigen expression in cells from treated IMT xenograft tumors. The combination of the ALK inhibitor crizotinib with BV has also been investigated. In vivo, the combination of crizotinib and BV resulted in complete resolution of tumor and significantly (p&amp;lt;0.0001) improved survival compared to the individual agents. Conclusion: CD30 is a promising therapeutic target in RANBP2-ALK-rearranged IMT. BV successfully reduced IMT cell viability in vitro and prolonged survival in IMT xenografted mice, both as a single agent and when given in combination with crizotinib. Since BV is current clinical use for the treatment of Hodgkin lymphoma it may be possible to rapidly translate these findings into clinical practice for the treatment of IMT. Citation Format: Ashleigh M. Fordham, James Blackburn, Erin E. Heyer, Jinhan Xie, Emily V. Mould, Andrew J. Gifford, Lisa T. Morgan, Carol Wadham, Mitali Fadia, Jamie I. Fletcher, Karen L. MacKenzie, Toby N. Trahair. Targeting CD30 as a novel treatment strategy in RANBP2-ALK-rearranged inflammatory myofibroblastic tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4824.