Year 3

Dormant cancer stem cells (CSC) evade therapies that target dividing cells and promote drug-resistance, relapse, and metastasis. Despite advances in molecularly targeted therapy, therapeutic resistance and relapse, driven by self-renewing CSC, remain major therapeutic challenges in common hematologic malignancies like chronic lymphocytic leukemia (CLL). As a result of a CIRM HALT leukemia disease team grant, we developed a monoclonal antibody, cirmtuzumab (UC-961), which targets the Wnt5A receptor, ROR1. Cirmtuzumab is a humanized monoclonal antibody (mAb) that binds with high-affinity to a proprietary, extracellular epitope of ROR1, which we defined as an onco-embryonic antigen. While ROR1 is not expressed on adult hematopoietic stem cells or other normal post-partum tissues, it is highly expressed on the cell-surface of CLL cells and CSC of a broad array of solid tumors. Cirmtuzumab does not bind to normal adult tissues, but has unique functional activity against leukemia cells and CSC by targeting ROR1. Cirmtuzumab inhibits the capacity of CSC to propagate CLL in immune-deficient mice. Finally, cirmtuzumab induced rapid internalization of ROR1, thereby inhibiting CSC survival. Based on these unique features, we proceeded with the cirmtuzumab clinical development plan under the auspices of the CIRM disease team 3 grant.

Our CIRM Disease team grant has enabled filing and FDA approval of an investigational new drug application (IND) for cirmtuzumab as well as the implementation and administration of an ongoing first-in-human Phase 1A clinical trial to assess safety and tolerability in patients with CLL who are not amenable to standard therapy. In keeping with the FDA IND-approved intra-patient dose escalation schema and related cirmtuzumab administration timeline, our team has enrolled 25 patients to the Phase lA clinical trial at UC San Diego for patients with relapsed or refractory CLL since 8/29/15. There have been no observed dose limiting toxicities attributed to cirmtuzumab. While complete responses have not been observed, we have observed biological activity and clinical benefit with stabilization of disease in some patients. Oncternal Therapeutics, Inc., a new oncology-focused biotechnology company, has licensed the rights to develop and commercialize antibodies and antibody-related binding agents recognizing ROR1 from University of California San Diego.