CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma

Abstract

Background Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. Methods Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. Results Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. Conclusions CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies

“…These tumours have an ALK fusion (mostly ALK-RANBP2 fusion) in a very high percentage of cases and very aggressive behaviour with a high risk of relapse [71e73]. Furthermore, the combination of crizotinib and brentuximab vedotin is more active in eIMS than the single agents, supporting the future development of this and other combinations clinically [74]. FDG-PET imaging may play an important role in monitoring the response to therapy and surveillance of these patients [30].…”

Molecular Targets for Novel Therapeutics in Pediatric Fusion-Positive Non-CNS Solid Tumors

“…In the diagnosis eIMS model, the majority of mice were confirmed as tumor-free 180 days past the study end date. However, disease recurrence was observed in all mice in the relapsed eIMS model, indicating that CD30 and ALK combination therapy may be most effective as early treatment for eIMS ( Fordham et al, 2020 ).…”

Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL

“…The most obvious mechanism of resistance is a reduction in CD30 protein expression, the target of BV activity. This has been observed in at least one case of adult ALK-negative ALCL [ 170 ] and in epithelioid inflammatory myofibroblastic sarcoma patient-derived xenografts (PDXs) [ 171 ]. It is unclear whether these reductions in CD30 were due to downregulation of the CD30 target, increased turnover of CD30, CD30 internalisation, or the selective outgrowth of sub-clones with lower levels of CD30 expression [ 171 ].…”

“…This has been observed in at least one case of adult ALK-negative ALCL [ 170 ] and in epithelioid inflammatory myofibroblastic sarcoma patient-derived xenografts (PDXs) [ 171 ]. It is unclear whether these reductions in CD30 were due to downregulation of the CD30 target, increased turnover of CD30, CD30 internalisation, or the selective outgrowth of sub-clones with lower levels of CD30 expression [ 171 ]. However, CD30 target reduction does not account for all BV resistance because CD30 expression is maintained in some BV-resistant Hodgkin lymphoma and ALCL [ 172 ].…”

“…However, CD30 target reduction does not account for all BV resistance because CD30 expression is maintained in some BV-resistant Hodgkin lymphoma and ALCL [ 172 ]. A second potential resistance mechanism is upregulation of ABC transporters, which has been demonstrated in BV-resistant Hodgkin lymphoma cell lines and patient samples [ 172 , 173 , 174 ], and epithelioid inflammatory myofibroblastic sarcoma PDXs [ 171 ]. However, this also cannot account for all BV resistance because Hodgkin lymphoma cells treated with BV and an MDR-1 inhibitor eventually stop responding to this combination [ 174 ].…”