Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia

Michael Y Choi; George F Widhopf 2nd; Emanuela M Ghia; Reilly L Kidwell; Md Kamrul Hasan; Jian Yu; Laura Z Rassenti; Liguang Chen; Yun Chen; Emily Pittman; Minya Pu; Karen Messer; Charles E Prussak; Januario E Castro; Catriona Jamieson; Thomas J Kipps

doi:10.1016/j.stem.2018.05.018

Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia

Cell Stem Cell. 2018 Jun 1;22(6):951-959.e3. doi: 10.1016/j.stem.2018.05.018.

Authors

Affiliations

¹ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; CIRM Alpha Stem Cell Clinic at University of California, San Diego, and Sanford Stem Cell Clinical Center, La Jolla, CA 92037-0695, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
² Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; CIRM Alpha Stem Cell Clinic at University of California, San Diego, and Sanford Stem Cell Clinical Center, La Jolla, CA 92037-0695, USA.
⁵ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093-0901, USA.
⁶ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; CIRM Alpha Stem Cell Clinic at University of California, San Diego, and Sanford Stem Cell Clinical Center, La Jolla, CA 92037-0695, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037-0695, USA. Electronic address: cjamieson@ucsd.edu.
⁸ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; CIRM Alpha Stem Cell Clinic at University of California, San Diego, and Sanford Stem Cell Clinical Center, La Jolla, CA 92037-0695, USA; Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tkipps@ucsd.edu.

Abstract

Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL.

Publication types

Clinical Trial, Phase I

MeSH terms

Antibodies, Monoclonal, Humanized / administration & dosage
Antibodies, Monoclonal, Humanized / chemistry
Antibodies, Monoclonal, Humanized / metabolism*
Antibodies, Monoclonal, Humanized / pharmacology
Antibodies, Monoclonal, Humanized / therapeutic use
Dose-Response Relationship, Drug
Drug Tolerance
Humans
Infusions, Intravenous
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Receptor Tyrosine Kinase-like Orphan Receptors / antagonists & inhibitors*
Receptor Tyrosine Kinase-like Orphan Receptors / genetics
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
Signal Transduction / drug effects*
Signal Transduction / genetics
Structure-Activity Relationship

Substances

Antibodies, Monoclonal, Humanized
ROR1 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors
cirmtuzumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding