13P - Universal prospects of cryopreserved umbilical cord blood CD34+ progenitor cell-derived NK cells: Clinical and preclinical evaluation of non-engineered and genetically engineered candidates

Background

Natural killer cells (NK) are gaining traction as (non-)engineered cell therapy products also used in combination therapies. Glycostem’s ex vivo expansion and differentiation method in a fully closed automated manufacturing platform (uNiK^TM), generates GTA002 (oNKord®), an “off-the-shelf” allogeneic cryopreserved NK cell product from umbilical cord blood-derived CD34⁺ progenitors. Safety and tolerability of a fresh predecessor was shown in a phase I trial in AML and a phase II trial of oNKord® in AML is now on-going. Recent preclinical assessments elucidate the capacity of GTA002 to target hematological and solid malignancies.

Methods

Potency assays in combination with receptor blocking monoclonal antibodies (mAb) for assessment of cytotoxicity and receptor involvement were performed in 2D by flow cytometry and in 3D spheroids by Incucyte. GTA002’s capacity to upregulate CD16a in vivo spurred the exploration of antibody-dependent cellular cytotoxicity ADCC against otherwise non-susceptible targets.

Results

GTA002 showed rapid cytotoxic responses against melanoma cell lines at low effector:target ratios. The involvement of several activating receptors, and specifically death receptor TRAIL, for efficient cytotoxicity was revealed. Multimodal activation for efficient cytotoxicity was verified in both 2D and 3D melanoma models. Pre-clinical results show rapid ADCC against HER2⁺ and CD19⁺ tumors within a few hours from target exposure to GTA002. 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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Glycostem Therapeutics.

Disclosure

A. Georgoudaki, N. Lamers-Kok, A. Van Vliet, D. Özkazanc, D. Vodegel, D. Steenmans, M. Raimo, A.D. Duru, J. Spanholtz: Financial Interests, Personal, Full or part-time Employment: Glycostem Therapeutics.