Year 2

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, which acts in a niche-dependent fashion. In preclinical models, shRNA-silencing of ROR1 could impair activation of phospho-AKT/CREB, thereby increasing the tendency for spontaneous apoptosis, and could inhibit the proliferation, migration, and metastatic potential of CSC in a manner similar to cirmtuzumab. In addition, 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 20 patients to the Phase lA clinical trial at UC San Diego for patients with relapsed or refractory CLL since 8/29/15. In particular, we have now completed enrollment of the first six cohorts. There have been no observed dose limiting toxicities attributed to cirmtuzumab given at 4 biweekly infusions over a 2-month period. While complete responses have not been observed, we have observed biological activity and clinical benefit with stabilization of disease in some patients. This has prompted the development of a Phase 1B clinical trial, currently under review at our IRB and at CIRM, to allow patients that have derived benefit from treatment with cirmtuzumab to receive additional doses and to determine if longer term treatment provides enhanced clinical benefit while retaining an excellent safety profile.

Correlative biomarkers include flow cytometric analyses that address disease heterogeneity and are suggestive of decreased ROR1 expression in the more recent dosing cohorts that may be used in the future to predict clinical outcome. In cohorts that demonstrate signs of sustained clinical responses, we will examine the activity of cirmtuzumab-based treatments in eradicating ROR1+ CSC by flow cytometry. Pharmacokinetic assessments are ongoing but cirmtuzumab plasma levels appear to correlate with response in the more recent higher dose cohort. In addition, we will examine the activity and anticipated therapeutic index (TI) of cirmtuzumab in relapsed/refactory CLL. If one or more of these tests meet milestones, then clinical studies of regimens with the highest apparent TI will be conducted in years 3-4. Upon completion of our program, we will deliver a cirmtuzumab-based therapeutic that will be suitable for registration and/or pivotal clinical trials and facilitate commercialization of this novel cancer stem-cell targeted therapy for Californians with cancer.

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. The licensing agreement encompasses rights for all therapeutic indications to cirmtuzumab, the anti-ROR1 monoclonal antibody that is currently in a clinical trial for patients with chronic lymphocytic leukemia (CLL), as well as rights to develop antibody-drug conjugates (ADCs), genetically modified effector immune cells, such as chimeric antigen receptor T-cells (CAR-T), and bispecific antibodies. The Oncternal leadership team has extensive experience in the formation and successful development of biotechnology companies and innovative pharmaceutical products.