| Autor: |
John M. Maris, Peter J. Houghton, Raushan Kurmasheva, Richard Gorlick, Brad St. Croix, Yang Feng, Steven Seaman, Yifei Wang, Samson Ghilu, Matthew Tsang, David Groff, Khushbu Patel, Kateryna Krytska, Jennifer Pogoriler, Daniel Martinez, Yael P. Mosse, Eric J. Earley, Stephen W. Erickson, Beverly A. Teicher, Malcolm A. Smith, E. Anders Kolb, Jarrett Lindsay, Nathan M. Kendsersky |
| Rok vydání: |
2023 |
| Popis: |
Purpose:Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3–targeting antibody–drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line–derived xenograft (CDX) models.Experimental Design:B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (N = 3), rhabdomyosarcoma (N = 4), Wilms tumors (N = 2), osteosarcoma (N = 5), and neuroblastoma (N = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD.Results:The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks.Conclusions:m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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