Session: 605. Molecular Pharmacology, Drug Resistance—Lymphoid and Other Diseases: Poster III
Hematology Disease Topics & Pathways:
Biological, antibodies, Adult, Diseases, Mantle Cell Lymphoma, Therapies, cell regulation, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Biological Processes, Technology and Procedures, immune cells, immunotherapy, Cell Lineage, Xenograft models, Lymphoid Malignancies, Study Population, Clinically relevant, flow cytometry, pathways, signal transduction
To assess total and cell surface ROR1 expression we used flow cytometry (FACS), western blot analysis, and reverse-transcriptase-polymerase chain reaction (RT-PCR). Cell viability and apoptosis assays were performed to evaluate the in vitro efficacy of VLS-101 in MCL cell lines and primary patient MCL samples. To assess the apoptosis and cell cycle arrest in cells treated with VLS-101, we used annexin V/propidium iodide-staining followed by flow cytometry analyses. In vivo efficacy was tested using various PDX models with various multiple resistances.
All 5 cell lines and all 9 PDX models of MCL tested showed high ROR1 mRNA and protein expression levels, whereas 3 out of 4 primary human samples expressed cell surface ROR1. VLS-101 treatment showed anti-MCL activity at the concentrations of 0.3-9 μg/ml in most of cell models tested, which correlated with a significant G2/M cell cycle arrest. Furthermore, VLS-101 induced a time- and dose-dependent apoptosis, as shown by increases in annexin V/propidium iodide-staining.
VLS-101 treatment of ibrutinib-venetoclax dual-resistant ROR1+ PDX model resulted in significant regressions of the tumor bearing spleens and livers when compared to vehicle controls (p=0.0001 and p=0.002 respectively). In the ibrutinib-CD19 CAR T dual-resistant ROR1+ model, vehicle-treated animals showed s.c. tumor masses with a mean volume of 1440 mm3, whereas tumor masses were barely palpable (mean = 160 mm3) or had completely regressed in animals treated with VLS-101 at 1.0 mg/kg or 2.0 mg/kg, respectively. VLS-101 showed no adverse effects as monitored by animal clinical observations and weekly body weight measurements.
Collectively, these results indicate that ROR1 expression on MCL cells can be utilized for selective targeting. These preclinical data document that the MMAE-containing ADC, VLS-101, can cause cell cycle arrest and induce apoptosis in vitro and safely induce tumor regressions in highly resistant in vivo PDX models of MCL derived from patient tumors. Importantly, our study revealed that even the heavyly pretreated tumors in the clinical setting may express targetable levels of ROR1 and that targeting ROR1 using ADC is a promising approach for the treatment of MCL. Building on these types of results, a Phase 1 clinical trial on VLS-101 (NCT03833180) is ongoing in patients with lymphoid cancers.
Disclosures: Jessen: VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Lannutti: VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Wang: Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; Lu Daopei Medical Group: Honoraria; Molecular Templates: Research Funding; Oncternal: Consultancy, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Pulse Biosciences: Consultancy; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; Nobel Insights: Consultancy; Verastem: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Guidepoint Global: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria.
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