Abstract 3038: Evaluation of ROR1-targeted antibody-drug conjugates against ROR1-expressing pediatric preclinical models - a report from the pediatric preclinical testing consortium (PPTC)
Authors: Lock Richard B. , Evans Kathryn , El-Zein Narimanne , Lannutti Brian J. , Jessen Katti A. , Earley Eric J. , Erickson Stephen W. , Smith Malcolm A. , Kurmasheva Raushan , Houghton Peter J. 
Published: July 2021

Abstract
Introduction: ROR1 is an orphan-receptor tyrosine kinase-like surface antigen that is expressed primarily during development but is not expressed on normal adult tissues. ROR1 is expressed on multiple adult hematologic and solid cancers, making it a target for antibody-based therapies. UC-961 (cirmtuzumab), a humanized IgG1 monoclonal antibody, binds with high affinity to a specific extracellular epitope of human ROR1 and rapidly internalizes and traffics to lysosomes. VLS-101 is an ADC developed by conjugating UC-961 to a cleavable linker with an MMAE payload. VLS-211 was generated by conjugating UC-961 with a PNU payload. VLS-101 is in clinical development for adults with hematologic and solid cancers and has received FDA Fast Track and Orphan Drug designation for the treatment of patients with mantle cell lymphoma. To better define the utility of ROR1 as an immuno-oncology target for pediatric cancers, we evaluated VLS-101 and VLS-211 against pediatric preclinical models selected based on ROR1 expression.
Methods: Models were selected based on RNA-seq transcript levels for ROR1 with subsequent confirmation by flow cytometry for acute lymphoblastic leukemia (ALL) models. For the ALL models, UC-961 (5 mg/kg), VLS-101 (2.5 and 5.0 mg/kg), and VLS-211 (0.25 and 0.5 mg/kg) were each administered weekly x 3. For the Ewing sarcoma (EWS) models, the dose of VLS-211 was 0.5 and 1 mg/kg. Four models were treated using a twice-weekly or every 4-day treatment schedule while 2 models were treated weekly.
Results: Elevated ROR1 gene expression among PPTC models was most notable among the ALL and EWS panels. Leukemia cell surface expression of ROR1 correlated with transcript levels. ALL models with elevated ROR1 expression [TCF3-HLF (1), TCF3-PBX1 (2), ETV6-RUNX1 (2), and BCR-ABL1 (1)] as well as a non-expressing model were tested against the ROR1 ADCs. Activity of each ADC was ROR1 expression-level dependent, and for VLS-211 dose-dependency was noted. At the highest doses of each ADC studied, 2 of 6 (VLS-101) and 3 of 6 (VLS-211) ROR1-expressing models showed objective responses. For most models, median time to event was longer for VLS-211 versus VLS-101. Five EWS models were studied, and expression-level dependent activity was observed for both ADCs. VLS-101 induced tumor regressions in 2 of 5 models, while VLS211 induced regressions in 3 of 5 models. Time to event was generally longer for VLS-211 compared to VLS-101. No objective responses were observed to UC-961 for the ALL and EWS models.
Conclusions: VLS-101 and VLS-211 showed expression-level dependent activity against ALL and EWS models. These results support ROR1 as a relevant immuno-oncology target for the subset of B-ALL and Ewing sarcoma cases with elevated ROR1 expression. Further research is required to identify the optimal payload for ROR1 ADCs for use against pediatric cancers.
Citation Format: Richard B. Lock, Kathryn Evans, Narimanne El-Zein, Brian J. Lannutti, Katti A. Jessen, Eric J. Earley, Stephen W. Erickson, Malcolm A. Smith, Raushan Kurmasheva, Peter J. Houghton. Evaluation of ROR1-targeted antibody-drug conjugates against ROR1-expressing pediatric preclinical models - a report from the pediatric preclinical testing consortium (PPTC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3038.