Year 4

The CIRM Alpha Stem Cell Clinic at UC San Diego has made several advances in spinal cord injury, diabetes, heart failure and cancer.

First, we have completed CIRM funded Phase 1 trials to evaluate the safety and tolerability of an antibody, cirmtuzumab, which targets an embryonic receptor, ROR1. This cancer stem cell survival and self-renewal pathway is expressed by a broad array of incurable malignancies. Cirmtuzumab has been tested in patients with chronic lymphocytic leukemia (CLL) and has provided important insights into mechanisms of cancer stem cell survival and metastasis. Results were published in Cell Stem Cell in 2018 and showed that decreased CLL burden and delayed time to next treatment coincided with reversal to a profile compatible with normal hematopoiesis. UCSD has partnered with Oncternal Therapeutics Inc., and through the Alpha Clinic has proceeded with a CLIN2 grant and Oncternal co-funded multi-center Phase 1b/2 trial combined with Ibrutinib to assess safety and efficacy in patients with refractory B cell malignancies. The Phase 2 trial has expanded to include other Alpha Clinics. Because of elevated ROR1 expression in high-risk breast cancer, we have launched a Phase 1b/2A study in combination with placlitaxel with co-funding from the Moores Cancer Center, a state grant to treat underrepresented minority populations, and Oncternal who is also providing cirmtuzumab.

Development of cellular immunotherapy trials is possible due to the Alpha Clinic’s pre-clinical regulatory expertise and operational activities. Specifically, a Phase 1 study of induced pluripotent stem cells derived NK cells sponsored by Fate Therapeutics has been launched for patients with advanced solid tumors and Alpha Clinic will support expanded enrollment. In addition, via an IRB Reliance, the dendritic cell vaccine trials for glioblastoma, sponsored by Aivita, was expanded from UCI’s Alpha Clinic to UCSD’s. There has also been expansion to include patients with advanced ovarian cancer. We have established a cell and regenerative medicine service to ensure that patients are appropriately monitored for immune-based adverse events both as inpatients and outpatients.

Second, a Phase 1A trial supported by Neuralstem Inc. and the Sanford Stem Cell Clinical Center 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. Proof-of-concept studies to evaluate neural repair and regeneration have been analyzed and published in Cell Stem Cell in 2018 with early evidence of spinal cord remyelination. Enrollment to the Phase 1B trial is near completion. This trial has helped to hone the requisite clinical trial expertise for initiating other acute spinal cord injury trials including the enhancement of endogenous repair with a scaffold developed by sponsor In Vivo. We have also initiated the Discgenics-sponsored trial of MSCs for single level disc herniation thereby adding to the interventional neurological repair pipeline.

Third, we have ongoing Phase 1 trials sponsored by ViaCyte, Inc. that evaluate safety, tolerability and biomarkers of response to devices containing human pluripotent stem cell derived pancreatic precursors implanted in diabetic patients. These studies have received support from CIRM Strategic Partnership and CLIN2 awards, the Sanford Stem Cell Clinical Center and Alpha Clinic.

Fourth, a Phase 3 trial to establish efficacy of a mesenchymal stromal cell product is currently being evaluated in patients with advanced congestive heart failure. As a result of Alpha Clinic involvement, accrual at UC San Diego has increased. The trial is sponsored by Mesoblast and has provided the impetus for developing stem cell and immune cellular imaging reagents for MRI detection developed by CIRM funded Professor Erich Ahrens and Nobel Laureate, Professor Roger Tsien.

Fifth, a Phase 1 trial of personalized, adoptive immunotherapy by cytotoxic T cells targeted to Myelodysplastic syndromes-specific cancer stem cell neoantigens sponsored by Persimmune has been initiated . The targeting of neoantigens to cancer stem cells is a paradigm-shifting and practice- changing cancer prevention strategy that has the potential to reduce the number of cases that advance to full blown acute myeloid leukemia. As a result of marrying cancer center activities to stem cell research activities it is possible to address an unmet medical need in a logical and safe manner.

We anticipate that the several CIRM, NIH and private foundation grants held by UC San Diego investigators will inform the development of pipeline 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.