Summary:Delayed engraftment, graft failure, and adverse transplant-related events have been observed in unrelated umbilical cord blood (UCB) recipients, particularly in those receiving a low leukocyte cell dose and in CML patients. We report the outcomes of two older adult patients with high risk CML who received a low leukocyte cell dose of unmanipulated UCB cells supplemented with ex vivo expanded (AastromReplicell System) UCB cells. Each engrafted promptly and neither patient experienced GVHD or life-threatening infection. Both remain engrafted with cells exclusively of donor origin and are in cytogenetic remission at 19 and 8 months follow-up. Ex vivo expanded UCB cells appear to facilitate hematopoietic recovery and therefore may increase the number of CML patients eligible for unrelated UCB transplant. Bone Marrow Transplantation (2000) 25, 797-799. Keywords: chronic myelogenous leukemia; umbilical cord blood transplant; ex vivo expansion Transplantation of umbilical cord blood (UCB) from related and unrelated donors has been performed in an attempt to increase the number of potential allogeneic stem cell donors. 1,2 The limited availability of unrelated donor UCB units of adequate nucleated cell dose, however, restricts its application in older adult patients. Ex vivo expansion of UCB in small and clinical-scale regulated perfusion experiments (AastromReplicell System, Ann Arbor, MI, USA) has been proven capable of significantly increasing the number of total nucleated cells, CFU-GM, and longterm culture initiating cells. 3 Therefore, the effect of supplementing unrelated donor UCB with ex vivo expanded UCB cells from the same donor was evaluated in two older adult patients with high risk CML and no alternative donor.

Summary:The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34 ؉ selection may delay platelet count recovery after high-dose chemotherapy and CD34 ؉ -enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m 2 i.v. and G-CSF 10 g/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34 ؉ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4؇C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34 ؉ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34 ؉ selection and cryopreservation. Median yield of CD34 ؉ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P ‫؍‬ 0.339). Neutrophil recovery Ͼ500 × 10 9 /l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P ‫؍‬ 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P ‫؍‬ 0.933). We conclude that storage of PBPC overnight at 4؇C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34 ؉ -selected progenitor cells. Bone Marrow Transplantation (2000) 25, 559-566.

Summary:To reduce the number of apheresis procedures and maintain the usual rate of hematopoietic recovery in patients treated with high-dose chemotherapy, we studied the effect of adding a small volume of ex vivo expanded bone marrow to low doses of CD34 + blood stem cells. Thirty-four patients with breast cancer received G-CSF (10 g/kg/day) priming followed by a limited volume (50-100 ml) bone marrow aspiration and standard 10-liter aphereses. Marrow was expanded ex vivo using the AastromReplicell system and infused along with low doses of blood-derived CD34 + cells, collected in one apheresis. Thirty-one evaluable patients received a median CD34 + blood stem cell dose of 0.7 × 10 6 /kg (range, 0.2-2.5) and 4.7 × 10 7 nucleated cells/kg (range, 1.98-8.7) of ex vivo expanded marrow. All patients recovered with normal blood counts and engrafted 500 neutrophils/l and 20 000 platelets/l in a median of 10 and 13 days, respectively. Multivariate analysis revealed that, in addition to CD34 + lineage negative cell quantity, the quantity of stromal progenitors contained in the ex vivo expanded product correlated with engraftment outcome (r = 0.551, P = 0.004

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Background CYNK-001 is a cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell investigational product derived from placental CD34+ cells. CYNK-001 exhibits cytotoxicity against various cancer cell types as well as virally infected cells and secretes immunomodulatory cytokines upon target activation. This is the first study to evaluate the safety and potential efficacy of CYNK-001 to treat patients (pts) with SARS-CoV-2, previously investigated in only solid tumor and hematologic malignancies. Methods Placental CD34+ cells were cultured in the presence of cytokines for 35 days to generate CYNK-001 under the cGMP conditions. Pts with a positive RT-PCR test for SARS-CoV-2 from the nasopharynx and having moderate to severe illness, not requiring intensive care support or mechanical ventilation, were eligible. All enrolled pts received best supportive care. In the Phase 1 trial focused on safety of administration, a total of 14 pts will receive up to 3 CYNK-001 infusions on Days 1 (1.5e8 cells), 4 (6e8 cells), 7 (6e8 cells). Efficacy was measured by SARS-CoV-2 clearance as measured by RT-PCR testing and clinical measures of improvement, including pulmonary status, and inflammatory marker changes. Results Four of 6 pts treated to date were evaluable at the time of submission. All had multiple medical co-morbidities. Peripheral oxygen saturation (Sp02) ranged between 88-92% on up to 8L of supplemental oxygen and all had evidence of multilobar pneumonia on chest radiography. Two pts had received no prior therapy for COVID-19. The other 2 pts received remdesivir and dexamethasone, with the 4th pt also receiving convalescent plasma. In all 4 pts, all infusions were well tolerated. In 3 of 4 pts, oxygenation improved after the first infusion of CYNK-001 and radiographic improvement was noted. The 4th pt developed progressive hypoxemia prior to the administration of the first dose of CYNK-001, requiring more than 30L of supplemental oxygen delivered by facemask to support a Sp02>90%. All 3 doses of CYNK-001 were administered, but oxygen requirements increased. Twelve days after first CYNK-001 dose, the pt declined mechanical ventilation and died of respiratory failure. Attribution to CYNK-001 could not be ruled out. The remaining 3 pts were discharged with an average follow-up of 16 (9-32) days after first infusion. Conclusion In the first study to measure the safety and potential efficacy of CYNK-001 infusions to treat pts with COVID-19 disease, infusions were generally well tolerated with one Grade 5 event of hypoxic respiratory failure. Early efficacy has been seen in 3 of 4 pts with improvement of oxygenation, inflammatory markers, and radiographic findings. Once Phase 1 is completed, the Phase 2 portion of the study will test this approach in a randomized fashion compared to best available therapy to confirm efficacy of this approach. Citation Format: Corey Casper, Leonid Groysman, Vinay Malhotra, Eric Whitman, Stacy Herb, Erica Rave, Alan Lew, Cristina Goman, Zachary Sagawa, Monica Thakar, Victoria Lacasse, Cherie Daly, Shuyang He, Lin Kang, Sharmila Koppisetti, Tanel Mahlakõiv, Sunday Osokoya, William van der Touw, Junhong Zhu, Greg Berk, Xiaokui Zhang, Andrew Pecora, Robert Hariri. Early report of a phase I/II study of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) for the treatment of adults with COVID-19 (NCT04365101) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT201.