The CIRM Alpha Stem Cell Clinic at UC San Diego has made several advances in cancer, spinal cord injury, diabetes and heart failure. Since the inception of our Alpha Stem Cell Clinic three years ago, the main goal has been to establish safety and tolerability of first-in-human stem cell research derived therapies, which are now in the process of transitioning to later stage cohorts and efficacy trials.
First, we have completed Phase 1A/B trials developed to evaluate the safety and tolerability of an antibody, cirmtuzmuab, 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 has been tested in patients with chronic lymphocytic leukemia (CLL) and has provided important insights into mechanisms of cancer stem cell survival and metastasis. In this CIRM funded trial, 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. As a result, Cirmtuzumab development has been partnered with Oncternal Therapeutics, Inc., and through the CIRM Alpha Stem Cell Clinic has proceeded with a CLIN2 grant (PI Kipps, Trial PI Jamieson) 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, including chronic lymphocytic and mantle cell lymphoma (CLL & MCL). Both CLL and MCL are typified by high level ROR1 expression. This trial will expand to include other Alpha Stem cell Clinic sites starting with City of Hope. 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 we expect to open in June 2018.
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, have been analyzed and included in a manuscript that is currently being revised for resubmission to Cell Stem Cell. The Phase 1B trial plan to accrue patients with cervical spinal cord injury to a higher cell dose cohort has been approved and has treated one patient with plans to include an additional 3 patients in this planned cervical spinal cord injury cohort. This study is supported by Neuralstem, Inc. and the Sanford Stem Cell Clinical Center.
Third, a Phase 1 trial to evaluate a device (EncaptraTM) containing human pluripotent stem cell derived pancreatic precursors is actively monitoring safety, tolerability and biomarkers of response in treated patients at the UCSD Alpha Stem Cell Clinic. Informative studies involving evaluation of pancreatic progenitor differentiation and insulin production following implantation provided the framework for development of a related device trial, PEC-Direct, which is ongoing at UC San Diego. This trial evaluates the products capability of enhancing angiogenesis within the graft. These studies are supported by ViaCyte, Inc., CIRM Strategic Partnership and CLIN2 awards 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 developing stem cell and immune cellular imaging reagents for MRI detection developed by CIRM funded Professor Erich Ahrens and Nobel Laureate, Professor Roger Tsien (Nature Materials, March 14, 2016).
Fifth, a phase 1 trial of personalized, adoptive immunotherapy by cytotoxic T cells targeted to Myelodysplastic syndromes (MDS)-specific cancer stem cell neoantigens has been initiated and enrolling patients. 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 (AML). 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.
The pipeline is primed with many grant-funded projects led by UC San Diego investigators for 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.