Year 2

First, we have almost completed a Phase 1A trial developed to evaluate the safety and tolerability of a CIRM funded antibody that targets an embryonic (WNT5A) receptor, ROR1. This cancer stem cell survival and self-renewal pathway is expressed by a broad array of incurable malignancies. Cirmtuzumab is currently being tested in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and has provided important insights into WNT5A/ROR1 mediated mechanisms of cancer stem cell survival and metastasis. In this CIRM funded trial, patients have had evaluation of biomarkers of response, including downstream ROR1 signaling targets, lymph node size, bone marrow responses and absolute lymphocyte count measurements. In keeping with cancer stem cell inhibition, we have begun to observe delayed time to progression and decreased leukemia burden in the bone marrow as well as inhibition of WNT5A/ROR1 signaling. Results from the Phase 1A trial, provided the impetus for a Phase 1B extended dosing trial that is currently accruing patients. As a result of phase 1 results, Cirmtuzumab development has been partnered with Oncternal Therapeutics Inc., a local biotechnology company, and through the CIRM Alpha Stem Cell Clinic plans to proceed with Phase 1b/2 trials combined with Ibrutinib to assess efficacy in patients with refractory B cell malignancies, including chronic lymphocytic and mantle cell lymphoma, which is also typified by high level ROR1 expression. We anticipate that this trial will expand quickly to include other Alpha Stem cell Clinic sites. Because of elevated ROR1 expression in high-risk breast cancer, we are working with Oncternal to establish a Phase 1B/2A trial of Cirmtuzumab combined with standard of care chemotherapy that may also be expanded to the Alpha Clinic Network.

Second, a Phase 1A trial to evaluate safety and tolerability of a neural stem cell product for chronic thoracic spinal cord injury has completed treatment of the first cohort of patients. The trial has provided key insights into factors that promote neural stem cell regeneration in areas of injury. Proof-of-concept studies to evaluate neural repair and regeneration, including quantitative measurements of recovery of neuronal function, are currently being analyzed. The Phase 1B trial plan to accrue patients with cervical spinal cord injury to a higher cell dose cohort has been approved by the FDA and has begun to screen patients. This study is supported by Neuralstem Inc and the Sanford Stem Cell Clinical Center. This trial has also helped to hone the requisite clinical trial expertise for initiating an Asterias-sponsored acute cervical spinal cord injury trial at UC San Diego in the near future.

Third, a Phase 1 trial to evaluate a device (EncaptraTM) containing human pluripotent stem cell derived pancreatic precursors (progenitors) is actively monitoring safety, tolerability and biomarkers of response in treated patients at our Alpha Stem Cell Clinic and has expanded to include another site at the University of Alberta in Canada. The trial has provided vital insights into mechanisms of impaired insulin production in type 1 diabetes. Studies to evaluate pancreatic progenitor differentiation and insulin production following implantation are ongoing and have provided the framework for development of a related device trial that is currently being evaluated at UC San Diego. This study is supported by ViaCyte, Inc., CIRM and the Sanford Stem Cell Clinical Center.

Fourth, a phase 3 trial to establish efficacy of a mesenchymal stromal cell (MSC) product is currently being evaluated in patients with advanced congestive heart failure. As a result of Alpha Stem Cell Clinic involvement, accrual has increased on the trial at UC San Diego. Efficacy endpoints will be reported at the time of study completion. The trial is sponsored by Mesoblast and has provided the impetus for a pipeline trial at the Alpha Clinic that will involve an innovative cellular imaging reagent for MRI developed by CIRM funded Professor Erich Ahrens and Nobel Laureate, Professor Roger Tsien (Nature Materials, March 14, 2016).

Finally, we anticipate that CIRM-funded stem cell discovery, translational and early phase clinical trial grants held by UC San Diego investigators will inform the development of pipeline Alpha Stem Cell Clinic Trials, involving cancer stem cell targeted immunotherapy, stem cell-based therapy for neurodegenerative disorders, stem cell gene therapy for inborn errors of metabolism and stem cell derived therapy for peripheral vascular disease.