Alpha Stem Cell Clinic for the Development of Regenerative Therapies

By accelerating translation of stem cell related discoveries to the clinic, the CIRM Alpha Stem Cell Clinic at UC San Diego has made several advances in the fields of diabetes, spinal cord injury, leukemia and heart failure. The majority of our trials represent Phase 1 trials and as with all Phase 1 trials, the main goal is to establish safety and tolerability of the approach. First, a first-in-human trial to evaluate the safety and tolerability of a device (EncaptraTM) containing human pluripotent stem cell derived pancreatic precursors (progenitors) is actively accruing 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. This study is supported by ViaCyte, Inc. and the Sanford Stem Cell Clinical Center. Second, a first-in-human trial to evaluate safety and tolerability of a neural stem cell product for thoracic spinal cord injury has completed treatment of the first cohort of patients and will proceed to the second cohort. 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 are ongoing. The protocol describing the plan to enroll the second cohort of patients at a higher cell dose is currently being evaluated by the FDA. This study is supported by Neuralstem Inc. and the Sanford Stem Cell Clinical Center. Third, 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 Teva 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, a first-in-human trial to evaluate the safety and tolerability of a CIRM funded antibody that targets an embryonic (Wnt5A) receptor, ROR1, which is re-expressed by a broad array of incurable malignancies is currently being tested in patients with relapsed or refractory chronic lymphocytic leukemia. The trial has provided important insights into Wnt5a/ROR1 mediated mechanisms of cancer stem cell survival and metastasis. The trial is actively accruing patients who will also have evaluation of biomarkers of response, including ROR1 internalization, lymph node size and absolute lymphocyte count measurements. Results from the Phase 1A trial have provided the impetus for the a Phase 1B extended dosing trial that is currently under review by our IRB and a Breast Cancer Research Foundation funded trial for advanced breast cancer in combination with Taxol that will be performed in our Alpha Stem Cell Clinic upon FDA approval of the IND. As a result of current phase 1 results, Cirmtuzumab development has been partnered with Oncternal Therapeutics Inc., a local biotechnology company, and through the CIRM Alpha Stem Cell Clinic for Phase 2 trials in advanced malignancies.

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.

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.

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.

The CIRM Alpha Stem Cell Clinic at UC San Diego has made several clinical trial advances in cancer, spinal cord injury, diabetes and heart failure. The main goal has been to establish safety, tolerability and proof of efficacy and we have transitioned a number of these trials to the proof of efficacy phases. Stem Cell Gene Therapy for Inherited Disorders A Phase 1, first-in-human CIRM funded clinical trial was launched at UCSD with Alpha Clinic support based on research conducted by UCSD’s Stephanie Cherqui and Edward Ball, and Donald Kohn (UCLA). This ex vivo transduced autologous human CD34+ hematopoietic stem cells for treatment of cystinosis culminated is an actively enrolling clinical trial at UCSD with Alpha Clinic support. Cancer Stem Cell Targeting with Cirmtuzumab As a result of encouraging phase 1 safety and proof-of-concept data, Cirmtuzumab partnered with Oncternal Therapeutics Inc. and through the CIRM Alpha Stem Cell Clinic launched a CLIN2 grant-funded trial (PI Kipps, Trial PIs Jamieson and Choi). This Phase 1b/2 trial of Cirmtuzumab combined with Ibrutinib focuses on assessing safety and efficacy in patients with refractory B cell malignancies. The phase 1 results of this trial showed that decreased chronic lymphocytic leukemia (CLL) burden and delayed time to next treatment coincided with reversal of the stemness index and reversion to more normal hematopoiesis RNA sequencing signatures. The Phase 2 trial for CLL and Mantle Cell Lymphoma (MCL) of Cirmtuzumab combined with ibrutinib has expanded to include other Alpha Stem Cell Clinic sites. We launched a Phase 1b/2a breast cancer study in combination with placlitaxel with Oncternal providing Cirmtuzumab and with co-funding from the Moores Cancer Center and more recently a state grant to treat underrepresented minority (URM) populations. T cell and iPS NK Cell Immunotherapy to Target Pre-Cancer and Cancer A first-in-human Phase 1 study of induced pluripotent stem cells (iPS) derived NK cells sponsored by FATE therapeutics has been launched for patients with advanced solid tumors. In addition, we are expanding the Aivita sponsored dendritic cell vaccine trials for glioblastoma multiforme (GBM) to ovarian cancer at UC San Diego and via an IRB reliance agreement with UCI’s Alpha clinic. To support these complex trials, we have also established a dedicated cell and regenerative medicine service (CRM) to ensure that patients are carefully monitored for immune-based adverse events both as inpatients and as outpatients. A phase 1 trial of personalized, adoptive immunotherapy by cytotoxic T cells (CTLs) targeted to Myelodysplastic syndromes (MDS)-specific pre-cancer stem cell neoantigens is enrolling patients and is sponsored by Persimmune. This 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. Neural Stem Cell Regeneration and Repair We completed a Phase 1 trial to evaluate safety and tolerability of a neural stem cell product sponsored by Neuralstem for chronic thoracic spinal cord injury patients. Proof-of-concept studies to evaluate neural repair and regeneration, including quantitative DT imaging and EMG measurements of recovery of neuronal function, showed early evidence of spinal cord remyelination. This trial has also helped to hone the requisite clinical trial expertise for initiating other acute spinal cord injury trials at UC San Diego including the enhancement of endogenous repair with scaffold with In Vivo. We have added to the interventional neurological repair portfolio by initiating the Discgenics-sponsored trial of MSCs for single level disc herniation. Stem Cell Derived Therapy for Metabolic Disorders Two Phase 1/2 trials to evaluate a device (EncaptraTM) containing human pluripotent stem cell derived pancreatic precursors, and a related device (PEC-Direct) are ongoing at UC San Diego. Treated patients at the UCSD Alpha Stem Cell Clinic are monitored for safety, tolerability and biomarkers of response. These studies are supported by ViaCyte, Inc., CIRM Strategic Partnership and CLIN2 awards as well as the Sanford Stem Cell Clinical Center. Immunomodulatory Mesenchymal Stromal Cell Therapy 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. 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.

The CIRM Alpha Stem Cell Clinic at UC San Diego has made several clinical trial advances in cancer, spinal cord injury, diabetes, inflammatory bowel disease and heart failure. The main goal has been to establish safety, tolerability and proof of efficacy and we have transitioned a number of these trials to the proof of efficacy phases. The UCSD Alpha Clinic portfolio currently consists of 18 open trials and 48 trial subjects have received or are receiving treatment on these active trials. The services of the Alpha Clinic that include regulatory submission and clinical trial coordination, together with the patient care provide by the Cell and Regenerative Medicine service and the Sanford Stem Cell Clinical Center, are integral to providing San Diego patients with experimental therapies in the regenerative medicine space that are not available anywhere else in the region. Due to the infrastructure established by the Alpha Clinic grant and complimented by infrastructure provided by UCSD and Sanford Stem Cell Clinical Center, we had an advantage that contributed greatly to the decision to the NASA award of $5 million in shared funding that Sanford Center received along with Space Tango for the project ‘Development of an Orbital Laboratory to Advance Stem Cell Therapies and Regenerative Medicine’. The improved US News and World Report rankings of UCSD released in 2021 are evidence that our institution’s reputation for innovative and compassionate patient care is top notch. The return on investment from the CIRM Alpha Clinic grant is considerable. Highlighted here are some of our most notable trials and accomplishments. Stem Cell Gene Therapy for Inherited Disorders A Phase 1, first-in-human CIRM funded clinical trial was launched at UCSD with Alpha Clinic support based on research conducted by UCSD’s Stephanie Cherqui and Edward Ball, together with Donald Kohn at UCLA. This ex vivo transduced autologous human CD34+ hematopoietic stem cells for treatment of cystinosis culminated in an actively accruing clinical trial at UCSD with Alpha Clinic support. Cancer 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. UCSD partnered with Oncternal Therapeutics Inc. and through the CIRM Alpha Stem Cell Clinic launched a CLIN2 grant-funded Phase 1b/2 trial of Cirmtuzumab combined with Ibrutinib focuses on assessing safety and efficacy in patients with refractory B cell malignancies. The phase 1 results of this trial showed that decreased chronic lymphocytic leukemia (CLL) burden and delayed time to next treatment coincided with reversal of the stemness index and reversion to more normal hematopoiesis RNA sequencing signatures. The Phase 2 trial for CLL and Mantle Cell Lymphoma (MCL) of Cirmtuzumab combined with ibrutinib ¬¬¬has expanded to include other Alpha Stem Cell Clinic sites and showed a 50% complete response rate with delayed time to progression. We launched and completed accrual for a Phase 1b/2a breast cancer study in combination with placlitaxel with Oncternal providing Cirmtuzumab and with co-funding from the Moores Cancer Center and more recently a state grant to treat underrepresented minority (URM) populations with evidence of delayed time to progression in some patients. A first-in-human Phase 1 study of induced pluripotent stem cells (iPS) derived NK cells sponsored by FATE therapeutics has been completed for patients with advanced solid tumors. In addition, we expanded the Aivita sponsored dendritic cell vaccine trials for glioblastoma multiforme (GBM) to ovarian cancer at UC San Diego and via an IRB reliance agreement with UCI’s Alpha clinic. To support these complex trials, we established a dedicated cell and regenerative medicine service (CRM) to ensure that patients are carefully monitored for immune-based adverse events both as inpatients and as outpatients. Neural Stem Cell Regeneration and Repair We completed a Phase 1 trial to evaluate safety and tolerability of a neural stem cell product sponsored by Neuralstem for chronic thoracic spinal cord injury patients. Proof-of-concept studies to evaluate neural repair and regeneration, including quantitative DT imaging and EMG measurements of recovery of neuronal function, showed early evidence of spinal cord remyelination. This trial has also helped to hone the requisite clinical trial expertise for initiating other acute spinal cord injury trials at UC San Diego including the enhancement of endogenous repair with scaffold from In Vivo. We have added to the interventional neurological repair portfolio by initiating the Discgenics-sponsored trial of MSCs for single level disc herniation. The expertise developed in the area of along with the surgical training facility at UCSD have established us as a highly recognized center for cellular product surgical delivery.

Since its inception in 2015, the UCSD CIRM Alpha Stem Cell Clinic (ASCC) has launched 30 trials (67% industry-sponsored), enrolled 275 patients, engaged a network of trial experts and accelerated patient accrual with ASCC network partners. Together, we have translated the $8.69 million CIRM ASCC grant and a $100 million T. Denny Sanford philanthropic gift to establish the Sanford Stem Cell Clinical Center (SSCCC) into $312.5 million in additional grants, philanthropy, and industry-sponsored clinical trials. The UCSD CIRM ASCC and the SSCCC teams have developed a unique design-to-delivery framework for clinical trial pipeline development in cancer, metabolic disease, and neurological disease. Our successful track record of clinical trial initiation and completion has been predicated on risk mitigation strategies that are built into the project from the earliest stages of planning and implementation. These efforts have led to achievement of important ASCC milestones, including launching a CIRM-funded Phase 1/2 stem cell gene therapy clinical trial for patients with cystinosis; completion of a Phase 1 spinal cord injury study that showed improvements in motor function; and FDA approval for a Phase 3 registration trial of a UCSD CIRM team-developed and CIRM and Oncternal-sponsored ROR1-targeting monoclonal antibody, Cirmtuzumab (Zilovertamab) for chronic lymphocytic leukemia that will provide biomarkers for IND enabling studies with a related CAR-T cell product. By leveraging UC San Diego Health’s location in a leading biotechnology hub, the UCSD CIRM ASCC has been able to maximize access and work collaboratively to refine regenerative medicine clinical trial protocols that will enhance clinical outcomes. For example, with our ASCC trial experts in Neurosurgery and Anesthesiology, we have established a collaboration with a local company to develop a Phase 2 trial of an hESC-derived oligodendrocyte precursors trial for patients with spinal cord injury. Moreover, by partnering early in the development of a switchable CAR-T cell product with Calibr, a non-profit translational research institute at Scripps, we are conducting the first-in-human study for refractory lymphoid malignancies with a blood and marrow transplant trial expert. To expand patient access, we helped to recruit City of Hope. The launch of the CIRM Alpha Stem Cell Clinic Network fostered the establishment of a robust and vigorous California state-wide infrastructure for the acceleration of clinical trials in regenerative medicine. UC Davis & City of Hope ASCCs UCD and COH ASCCs are sites in a multi-center Phase 1b/2 trial that is testing a cirmtuzumab/ibrutinib combination therapy for patients with B-cell lymphoid malignancies with UCSD serving as the reliant site (Oncternal, NCT03088878). City of Hope ASCC UCSD ASCC served as a site for a COH-initiated Phase 1 multi-center trial testing AB-205, a cell therapy consisting of human engineered cord blood endothelial cells, in adults with Hodgkin or non-Hodgkin lymphoma following autologous stem cell transplantation (Angiocrine, NCT03925935; COH reliant site). Our site also supported recruitment for a COH clinical study testing the use of blood plasma as a potential treatment for COVID-19 (NCT04497779). Our site collaborates with the UCLA ASCC in manufacturing for a Phase 1/2 study to test a stem cell gene therapy for cystinosis (NCT03897361; UCSD ASCC). The UCLA GMP facility oversees manufacturing of cells transfected with lentiviral vectors for this trial. In addition, UCSD supported UCLA in a compassionate use IND filing that cross-referenced IND# 117975, held by UCSD trial expert Thomas Kipps, for a study of cirmtuzumab in patients with relapsed or refractory chronic lymphocytic leukemia (NCT02222688). The close relationship between our ASCC sites facilitated the rapid transfer of all required documents for IRB approval at UCLA as well as delivery of the study drug cirmtuzumab. UCSD ASCC, in addition to UCD ASCC, were sites in a multi-center Phase 2 study initiated by UCI that tested autologous dendritic cells loaded with autologous tumor associated antigens for treatment of newly diagnosed glioblastoma (AIVITA, NCT03400917; UCI reliant site). The CIRM ASCC Network has developed innovative tools that have overcome many barriers to patient access and accelerated trial initiation and completion. There is great potential to build and expand upon these robust, existing Network relationships in several areas including manufacturing, community engagement, data platforms, education and training, specialized clinical trial cores, and in platforms supporting capacity building and quality improvement. The commitment to continue to work together as a Network to work to better serve Californians has been memorialized in a group letter to CIRM. We firmly believe that preferential utilization of the ASCC network by study sponsors will result and that patients, sponsors and health care providers will benefit.