The B7-H3–Targeting Antibody–Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models

Abstract

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.

The Role of CD276 in Cancers

“…In addition, m276-PBD dimer has shown extensive tumor killing effects and antimetastasis activity in vivo (25). In a recent study conducted by Nathan et al (79) a new CD276 targeting ADC m276-SL-PBD was introduced and its activity was explored in both pediatric solid malignancy patient-derived xenograft (PDX) and cell linederived xenograft (CDX) models. Significant anti-tumor activity of m276-SL-PBD was observed in PDX models of solid tumors including Ewing sarcoma, rhabdomyosarcoma, Wilms tumors, osteosarcoma, and neuroblastoma.…”

Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

“…This mechanism may be controlled in PD-L1 expressing pediatric tumors by combining NK cell treatment with PD-1 checkpoint inhibitors, although the expression of PD-1 on NK cells remains controversial [ 78 ]. Although there are preclinical studies that show the benefit of immune checkpoint inhibition, there are currently no FDA approved PD-L1 inhibitors for pediatric solid tumors [ 77 , 79 , 80 , 81 ]. Nivolumab and pembrolizumab have been used in phase 1 and 2 trials for pediatric patients with relapsed malignancies, but only pembrolizumab is approved for use in children with mismatch repair deficiency/microsatellite instability or Hodgkin lymphoma.…”

A Novel Orthotopic Implantation Technique for Osteosarcoma Produces Spontaneous Metastases and Illustrates Dose-Dependent Efficacy of B7-H3-CAR T Cells

“…We show that collagen-tumor cell scaffolds surgically implanted into the tibia of mice reliably produced local and systemic metastatic OS. Likewise, we demonstrate that CAR T cells targeting B7-H3, a tumor antigen that is expressed in a high percent of OS ( 15 – 17 ), have antitumor activity in a dose dependent fashion against primary and metastatic OS. Thus, the described model should be highly relevant for the preclinical evaluation and optimization of cell-based immunotherapies.…”

“…To establish CAR T cell activity against OS in our novel spontaneously metastasizing orthotopic model ( Figures 1A–I ), we first evaluated their function ex vivo . We chose to target B7-H3 in these studies because B7-H3 i) is highly expressed in a majority of OS samples ( 15 – 17 ), ii) is associated with OS progression/metastasis ( 22 ), and iii) has limited expression in normal human tissues ( 15 , 16 , 23 , 24 ). Likewise, the LM7 OS cell line ( 25 ) we used to develop this model expresses high levels of B7-H3 ( Figure 2A ).…”