oNKord (inaleucel) / Glycostem, Radboud University, Medac, Korea Kolmar - LARVOL DELTA

Umbilical cord blood CD34+ hematopoietic stem cell-derived natural killer cells in Acute Myeloid Leukemia – a phase I clinical study (ASH 2025) - P=N/A, P1/2 | "Background : The use of fresh umbilical cord blood (UCB) CD34+ hematopoietic stem cell (HSC)-derivedallogeneic natural killer (NK) cells has shown favorable safety in a phase I clinical trial in patients withacute myeloid leukemia (AML). In a multicenter, open-label, phase I study (NCT04632316) we evaluated the safety and efficacyof cryopreserved UCB CD34+ HSC-derived NK cells, inaleucel (oNKord®), after lymphodepletingconditioning regimen of cyclophosphamide/fludarabine (Cy/Flu) (for cohorts A1, A2, A3, A5), orazacitidine/venetoclax (Aza/Ven) (A4) followed by 1, 2 or 3 NK cell infusions in AML patients. One to three infusions of cryopreserved UCB CD34+ HSC-derived NK cells, inaleucel, in MRDpositive AML patients were determined safe and well tolerated. Based on these promising signs of safetyand efficacy dose expansion with Cy/Flu pre-conditioning is planned for the near future."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Pneumonia • Respiratory Diseases • CD34 • IDH2 • IL2 • IL6 • PTPRC • TP53

Closed-system manufacturing of therapeutic NK cells using automated cell enrichment and concentration processes enables scalable, robust and cost-effective solutions. (PubMed, Front Bioeng Biotechnol) - "Allogeneic therapeutic natural killer (NK) cells can be generated from umbilical cord blood (UCB)-derived CD34+ hematopoietic stem cells in a closed, semi-automated process...This study presents an agile solution using a single piece of equipment during two steps of a complex NK cell manufacturing process. This approach ensures closed system safety, automation, high consistency, and cost-effectiveness, enabling the successful delivery of high-quality allogeneic NK cell therapies to patients."

HEOR • Journal • Immunology • Oncology • CD34

INTRO: Intraperitoneal Infusion of ex Vivo-cultured Allogeneic NK Cells in Recurrent Ovarian Carcinoma Patients (clinicaltrials.gov) - P1 | N=11 | Completed | Sponsor: Radboud University Medical Center | Recruiting ➔ Completed

Trial completion • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • MUC16

NK4AML: Natural Killer-cell Therapy for Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=23 | Recruiting | Sponsor: Radboud University Medical Center | Trial completion date: Sep 2023 ➔ Sep 2025 | Trial primary completion date: Sep 2023 ➔ Sep 2025

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IL2

Qualification of a flow cytometry-based method for the evaluation of in vitro cytotoxicity of GTA002 natural killer cell therapy. (PubMed, Heliyon) - P1/2 | "Notably, we identified relevant aspects to address when progressing towards method validation to support pivotal clinical studies. This article provides a "case-study" of how analytical method development for cell therapeutics is planned and executed from early clinical stages, anticipating the need to establish robust procedures to overcome scientific and regulatory challenges during method validation."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Engineering of CD34+ progenitor-derived natural killer cells with higher-affinity CD16a for enhanced antibody-dependent cellular cytotoxicity. (PubMed, Cytotherapy) - "Together, these data demonstrate that the applicability of adoptive NK cell immunotherapy may be broadened to less NK-sensitive malignancies by upregulation of CD16a expression in combination with the use of tumor-targeting monoclonal antibodies."

IO biomarker • Journal • Gene Therapies • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD34 • FCGR3A • IFNG • NCAM1

Single-cell transcriptomics, proteomics and in vitro cytotoxicity of allogeneic cryopreserved natural killer cell therapy GTA002 identify potent effector signatures (SITC 2023) - P1/2 | "Conclusions In summary, this research contributes to the advancement of NK cell therapies by generating a deep understanding of the cells’ mechanism of action, and by linking it to features that can be measured during product manufacturing and QC. Notably, such pipeline is applicable to NK cell therapies from different sources, as well to genetically engineered products."

Preclinical • Acute Myelogenous Leukemia • Oncology • CD34

Combination therapy with stem cell derived natural killer cells and monoclonal antibodies leads to potent ADCC through engagement of endogenouse CD16 (SITC 2023) - P1/2 | "Addition of cytokine support further enhanced both baseline cytotoxicity as well as ADCC, leading to complete eradication of the SKOV-3 tumor cells. Conclusions Overall, the enhancement of the inherent potency of GTA002 by harnessing ADCC through combination therapy with mAbs achieved efficient Ag-specific responses demonstrating the great potential of multimodal targeting against a variety of challenging cancers using a highly safe ‘off-the-shelf’ NK cell-based cellular therapeutic."

Combination therapy • Acute Myelogenous Leukemia • Oncology • Ovarian Cancer • Solid Tumor • CD34 • GZMB • HER-2 • IFNG

Early TRAIL-engagement elicits potent multimodal targeting of melanoma by CD34 progenitor cell-derived NK cells. (PubMed, iScience) - "Umbilical cord blood (UCB) CD34 progenitor cell-derived natural killer (NK) cells exert efficient cytotoxicity against various melanoma cell lines...Strikingly, combinatorial receptor blocking led to more pronounced inhibition of cytotoxicity (up to 95%) than individual receptor blocking, especially in combination with TRAIL-blocking, suggesting synergistic cytotoxic NK cell activity via engagement of multiple receptors which was also confirmed in a spheroid model. Importantly, lack of NK cell-related gene signature in metastatic melanomas correlates with poor survival highlighting the clinical significance of NK cell therapies as a promising treatment for high-risk melanoma patients."

Journal • Melanoma • Oncology • Solid Tumor • CD34 • GZMB • IFNG • NKG2D

Superior Cytotoxic Signatures of Cord Blood Stem Cell-Derived Natural Killer Cell Therapeutics Identified with Bulk and Single-Cell Transcriptomics Analysis (ASGCT 2023) - P1/2 | "Glycostem Therapeutics has developed a closed, automated, and feeder-free system (uniK™) for ex vivo expansion and differentiation of umbilical cord blood-derived CD34+ stem cells into highly functional, cryopreserved, truly off-the-shelf GTA002 NK cells, currently evaluated in a Phase I/II clinical study in AML, WiNK (NCT04632316)...Identification of biomarkers of excellent batches can then be linked to therapeutic efficacy, to provide the most appropriate product to a given patient. This research contributes to the development of universal cell therapies by generating a deep understanding of underlying donor- or process-induced variability, which is highly relevant and applicable to products originating from different sources, like induced pluripotent stem cells-derived NK cells (iPSC-NK)."

Acute Myelogenous Leukemia • Oncology • CD34

NK4AML: Natural Killer-cell Therapy for Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=23 | Recruiting | Sponsor: Radboud University Medical Center | Trial primary completion date: Jun 2023 ➔ Sep 2023

Combination therapy • IO biomarker • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IL15 • IL2 • IL6 • IL7 • LAMP1

Universal prospects of cryopreserved umbilical cord blood CD34+ progenitor cell-derived NK cells: Clinical and preclinical evaluation of non-engineered and genetically engineered candidates (ESMO-TAT 2023) - "Furthermore, approaches to genetically equip GTA002 with chimeric antigen receptors to generate viveNK TM cells, recently showed efficient preclinical antigen-specific targeting of HER2 + and CD19 + tumors, while preserving innate NK cell cytotoxicity. Conclusions Overall, the preclinical innate performance and ADCC of cryopreserved “off-the-shelf” oNKord® cells as well as the cytotoxicity of viveNK TM cells demonstrate the great potential of multimodal targeting against a variety of cancer indications, and open up opportunities for combination therapies with a vast array of established mAb therapeutics and bispecific NK cell engagers."

Preclinical • Acute Myelogenous Leukemia • Melanoma • Oncology • Solid Tumor • CD19 • CD34 • FCGR3A • HER-2

Cord blood CD34+ stem cells are efficiently transduced with anti-CD19-CAR and expanded and differentiated into viveNK™ Natural Killer cells which display selective cytotoxicity against B-cell leukemia (SITC 2022) - P1/2 | "Glycostem Therapeutics has developed a closed, automated, and feeder-free system for ex vivo expansion and differentiation of umbilical cord blood-derived CD34 + stem cells into highly functional NK cells, currently evaluated in a Phase I/II clinical study (ClinicalTrials.gov ID: NCT04632316 )...Additionally, inherent innate NK cell phenotype and responses and the mechanism of action driving CD19-CAR viveNK™ cytotoxicity were investigated via flow cytometry-based analysis and single-cell RNA-sequencing (scRNA-Seq) of CAR-transduced vs non-transduced donors. Conclusions Our data show how off-the-shelf, highly functional, and antigen-directed CAR-NK cells can be generated ex vivo, offering an option to target cancers which are often resistant or difficult to treat with standard immunotherapy."

IO biomarker • Hematological Malignancies • Leukemia • Oncology • CD34

EARLY SAFETY AND CLINICAL COURSE OF PATIENTS WITH ACUTE MYELOID LEUKEMIA AND MEASURABLE RESIDUAL DISEASE RECEIVING GTA002, AN OFF-THE-SHELF, EX VIVO-CULTURED ALLOGENEIC NK CELL PREPARATION (EHA 2022) - P1/2 | "GTA002 is infused after a conditioning regimen of cyclophosphamide (Cy) and fludarabine (Flu) from day -5 to -3 at 300 and 30 mg/m 2 , respectively, with no subsequent planned antileukemic treatment. Conclusion GTA002 treatment of AML patients in CR/CRi with MRD was well tolerated with manageable side effects of the conditioning therapy. Even at the lowest dose level, periods of MRD negativity could be documented by MFC and NGS adding to the excitement of the evaluation of allogeneic, off the shelf NK cell-based immunotherapies in hematological malignancies."

IO biomarker • Preclinical • Residual disease • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Leukopenia • Metabolic Disorders • Neutropenia • Oncology • Thrombocytopenia • Transplantation • CD34 • IDH2 • NPM1 • PTPN11 • SRSF2 • TP53

Single-Cell Profiling Reveals Functional Heterogeneity and Serial Killing in Human Peripheral and Ex Vivo-Generated CD34+ Progenitor-Derived Natural Killer Cells. (PubMed, Adv Biol (Weinh)) - "By assessing the cytotoxic dynamics, it is shown that single umbilical cord blood-derived CD34+ hematopoietic progenitor (HPC)-NK cells display superior antitumor cytotoxicity. With an integrated analysis of cytotoxicity and cytokine secretion, it is shown that target cell interactions augment cytotoxic as well as secretory behavior of NK cells. By providing an integrated assessment of NK cell functions by microfluidics, this study paves the way to further functionally characterize NK cells ultimately aimed to improve cancer immunotherapy."

Heterogeneity • Journal • Preclinical • Oncology • CD34

INTRO: Intraperitoneal Infusion of ex Vivo-cultured Allogeneic NK Cells in Recurrent Ovarian Carcinoma Patients (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Radboud University Medical Center | Unknown status ➔ Recruiting | Trial completion date: May 2020 ➔ Oct 2023 | Trial primary completion date: May 2020 ➔ May 2023

Enrollment open • Preclinical • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • MUC16

Glycostem and medac enter into license, manufacturing, supply and commercialization agreement for Glycostem's lead product - oNKord (PRNewswire) - "Glycostem Therapeutics B.V...and medac GmbH...will partner to commercialize Glycostem's lead product, oNKord®. oNKord® is currently in a phase I/II clinical trial across 10 hospitals in 5 European countries....Under the terms of the agreement, medac receives an exclusive license to commercialize oNKord® in the EU, the UK and further European countries for acute myeloid leukemia (AML) and multiple myeloma (MM) patients."

Licensing / partnership • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

Registry of Patients Having Received oNKord® (clinicaltrials.gov) - P=N/A | N=50 | Recruiting | Sponsor: Glycostem Therapeutics BV | Not yet recruiting ➔ Recruiting | Initiation date: Mar 2022 ➔ Jun 2022

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies

Glycostem announces new data presentation at EHA 2022 Congress highlighting early safety and clinical course of oNKord in patients with Acute Myeloid Leukemia (PRNewswire) - "Glycostem Therapeutics B.V...today announced that an abstract on further findings of patients treated in its phase I/IIa WiNK trial have been accepted and will be presented at the European Hematology Association (EHA) 2022 Congress, which will take place 9th – 12th June 2022 in Vienna, Austria..."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Universal prospects of cryopreserved “off-the-shelf” umbilical cord blood CD34+ progenitor cellderived NK cell therapeutics: clinical and preclinical evaluation of GTA002 and genetically modified candidates (CIMT 2022) - P1/2 | "Furthermore, we implemented lentiviral-based chimeric antigen receptor (CAR) expression to the ex vivo expansion and differentiation platform and generated CAR-NK cells demonstrating preclinical antigen-specific targeting of GBM and CRC while preserving innate NK cell characteristics. Overall, preclinical and clinical performance of cryopreserved “off-the-shelf” GTA002 cells as well as CAR-NK cells demonstrate great potential of multimodal targeting various cancers."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Brain Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Glioblastoma • Hematological Disorders • Hematological Malignancies • Melanoma • Oncology • Solid Tumor • Transplantation • CD34 • PTPN11

Ex vivo expanded NK cells show potent anti-tumor activity against melanoma using a combination of multiple activating mechanisms (CIMT 2022) - "Our data show that GTA002 NK cells exert efficient anti-tumour activity against melanoma cell lines in vitro. The killing mechanism of GTA002 is dependent on a combination of multiple activating receptors and seem to synergize their downstream activation signalling."

Preclinical • Melanoma • Oncology • Solid Tumor • GZMB • IFNG • NKG2D • TNFA

Registry of Patients Having Received oNKord® (clinicaltrials.gov) - P=N/A | N=50 | Not yet recruiting | Sponsor: Glycostem Therapeutics BV

New trial • Acute Myelogenous Leukemia • Hematological Malignancies

Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90. (PubMed, Front Mol Biosci) - "Here, we describe the use of a blood-brain barrier (BBB) permissive supramolecular cationic drug vehicle comprising an inhibitor of the chaperone heat shock protein 90 (Hsp90), which sustains a cytotoxic effect on GBM cells, boosts the expression of MICA/B and ULBPs on the residual population, and augments the activity of clinical-grade aNK cells (GTA002)...Using a longitudinal in vitro model, we demonstrate >350% relative cell killing is achieved in SCI-101-treated cell lines compared to vehicle controls. In summary, these data provide a first-of-its-kind BBB-penetrating, long-acting inhibitor of Hsp90 with monotherapy efficacy, which improves response to aNK cells and thus may rapidly alter the treatment paradigm for patients with GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CD34 • HSP90AA1

Glycostem announces initial clinical data to be presented at 2021 ASH Annual Meeting (PRNewswire) - P1/2a; N=33; WiNK (NCT04632316); Sponsor: Glycostem Therapeutics BV; "The first patient converted to measurable residual disease (MRD) negativity (<0.1%) as assessed by multiparametric flowcytometry (MFC) on bone marrow on day 0, which was sustained at 1, 2, 3 and 6 months...Results in BM showed that NPM1 MRD was detectable at month 1 but was cleared at months 3 and 6. The second patient showed MRD positivity in BM by MFC at screening and on day 0, which turned to MRD negativity at month 1, turning positive again at month 2 and 3. Assessments in PB and BM by MRD-NGS showed that a IDH2 and a SRSF2 clone persisted after preconditioning and GTA002 infusion, but that a PTPN11 clone became undetectable in PB by Day 0 and in BM by month 2 and month 3."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] A PROSPECTIVE PHASE I/IIA TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF GTA002, AN OFF-THE-SHELF, EX VIVO-CULTURED ALLOGENEIC NK CELL PREPARATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (WINK TRIAL) (EHA 2021) - P1/2 | "After providing informed consent, patients enrolled in the clinical trial receive a lymphodepleting conditioning regimen consisting of cyclophosphamide and fludarabine followed by up to 3 NK cell infusions 4 days apart and will be followed up for 12 months. Preliminary safety data from the first cohort will be discussed at the meeting. Conclusion The overall objective of the trial is to evaluate whether GTA002 is safe and if it can eradicate MRD, thereby reducing the relapse risk and mortality in subjects with AML who are in CR with MRD and who do not proceed to allogeneic HSCT."

P1/2 data • Preclinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CD34