oNKord (inaleucel)

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.

P1, N=11, Completed, Radboud University Medical Center | Recruiting --> Completed

P1/2, N=23, Recruiting, Radboud University Medical Center | Trial completion date: Sep 2023 --> Sep 2025 | Trial primary completion date: Sep 2023 --> Sep 2025

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.

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.

P1/2, N=23, Recruiting, Radboud University Medical Center | Trial primary completion date: Jun 2023 --> Sep 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.

P1, N=12, Recruiting, Radboud University Medical Center | Unknown status --> Recruiting | Trial completion date: May 2020 --> Oct 2023 | Trial primary completion date: May 2020 --> May 2023

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.

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.

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.

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.