oNKord (inaleucel)

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.

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.

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.

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.

We believe that this correlation will help to identify the killings mechanisms of GTA002 as an allogeneic cellular therapy. Conclusion Our experimental data provide preclinical in vitro evidence for further investigation of the potential of adoptive NK cell therapy against glioblastoma.

We aimed to investigate whether our GTA002 NK cell product, expanded and differentiated ex vivo from cord-blood derived CD34+ hematopoietic stem cells, will in vitro effectively kill target various MM cell lines...Representative model MM cell lines were chosen based on their sensitivity/resistance to lenalidomide, bortezomib (BTZ) and CD38 surface expression, latter associated with responsiveness to daratumumab treatment: MM.1S, LP1, NCI-H292, OPM2, RPMI-8226, U266B1, KMS11 and KMS11/BTZ...More importantly, we observed high killing efficiency also in U266B1 cells with low CD38 expression, which is indicative of the refractoriness to daratumumab therapy. Conclusion Our experimental data show proof of efficient cytotoxic capacity of ex vivo expanded NK cells against MM in vitro, and a strong indication that they can provide a novel source of cellular immunotherapy used to treat MM patient target groups with unmet medical needs, including those with relapsed refractory disease.

We believe that this correlation will help to identify the killings mechanisms of GTA002 as an allogeneic cellular therapy. Conclusion Our experimental data provide preclinical in vitro evidence for further investigation of the potential of adoptive NK cell therapy against glioblastoma.

We believe that this correlation will help to identify the killings mechanisms of GTA002 as an allogeneic cellular therapy. Conclusion Our experimental data provide preclinical in vitro evidence for further investigation of the potential of adoptive NK cell therapy against glioblastoma.

We aimed to investigate whether our GTA002 NK cell product, expanded and differentiated ex vivo from cord-blood derived CD34+ hematopoietic stem cells, will in vitro effectively kill target various MM cell lines...Representative model MM cell lines were chosen based on their sensitivity/resistance to lenalidomide, bortezomib (BTZ) and CD38 surface expression, latter associated with responsiveness to daratumumab treatment: MM.1S, LP1, NCI-H292, OPM2, RPMI-8226, U266B1, KMS11 and KMS11/BTZ...More importantly, we observed high killing efficiency also in U266B1 cells with low CD38 expression, which is indicative of the refractoriness to daratumumab therapy. Conclusion Our experimental data show proof of efficient cytotoxic capacity of ex vivo expanded NK cells against MM in vitro, and a strong indication that they can provide a novel source of cellular immunotherapy used to treat MM patient target groups with unmet medical needs, including those with relapsed refractory disease.

We aimed to investigate whether our GTA002 NK cell product, expanded and differentiated ex vivo from cord-blood derived CD34+ hematopoietic stem cells, will in vitro effectively kill target various MM cell lines...Representative model MM cell lines were chosen based on their sensitivity/resistance to lenalidomide, bortezomib (BTZ) and CD38 surface expression, latter associated with responsiveness to daratumumab treatment: MM.1S, LP1, NCI-H292, OPM2, RPMI-8226, U266B1, KMS11 and KMS11/BTZ...More importantly, we observed high killing efficiency also in U266B1 cells with low CD38 expression, which is indicative of the refractoriness to daratumumab therapy. Conclusion Our experimental data show proof of efficient cytotoxic capacity of ex vivo expanded NK cells against MM in vitro, and a strong indication that they can provide a novel source of cellular immunotherapy used to treat MM patient target groups with unmet medical needs, including those with relapsed refractory disease.

We believe that this correlation will help to identify the killings mechanisms of GTA002 as an allogeneic cellular therapy. Conclusion Our experimental data provide preclinical in vitro evidence for further investigation of the potential of adoptive NK cell therapy against glioblastoma.

We aimed to investigate whether our GTA002 NK cell product, expanded and differentiated ex vivo from cord-blood derived CD34+ hematopoietic stem cells, will in vitro effectively kill target various MM cell lines...Representative model MM cell lines were chosen based on their sensitivity/resistance to lenalidomide, bortezomib (BTZ) and CD38 surface expression, latter associated with responsiveness to daratumumab treatment: MM.1S, LP1, NCI-H292, OPM2, RPMI-8226, U266B1, KMS11 and KMS11/BTZ...More importantly, we observed high killing efficiency also in U266B1 cells with low CD38 expression, which is indicative of the refractoriness to daratumumab therapy. Conclusion Our experimental data show proof of efficient cytotoxic capacity of ex vivo expanded NK cells against MM in vitro, and a strong indication that they can provide a novel source of cellular immunotherapy used to treat MM patient target groups with unmet medical needs, including those with relapsed refractory disease.

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.

Tumor antigen positive cell lines were subsequently targeted by CAR NK cells (GTA102) to investigate the efficiency of antigen-specific targeting of resistant tumor cells. It is essential to evaluate the potency of cell-based immunotherapy products in both 2D and 3D settings to target solid tumors efficiently. Most importantly, our results demonstrate that introduction of CAR to NK cells significantly improves targeting of UCB-NK cell resistant antigen+ CRC cells and stands out as a potential cell therapy product for the treatment of colorectal cancer patients.

Our data show that GTA002 NK cells exert efficient anti-tumour activity against melanoma cell lines in vitro. In order to better understand the differences in susceptibility to NK cell mediated killing between the different melanoma cell lines, we will further investigate the involvement of different killing mechanisms taking into account the contribution of the individual ligand expression profile of melanomas to NK cell activation.

P1/2, N=24, Recruiting, Radboud University | Not yet recruiting --> Recruiting

P1/2, N=24, Not yet recruiting, Radboud University