Synthetic Natural Killer Cells for Immunotherapy

Project Information

SYNKIT

Grant agreement ID: 838909

DOI

10.3030/838909

Project closed

EC signature date 19 March 2019

Start date 1 September 2020

End date 31 August 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 191 852,16

EU contribution

€ 191 852,16

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - SYNKIT (Synthetic Natural Killer Cells for Immunotherapy)

Reporting period: 2020-09-01 to 2022-08-31

Summary of the context and overall objectives of the project

Cancer remains a leading cause of death worldwide, urging for the development of innovative therapies to help patients. Recent advances have shown that infusion of immune cells, which possess an intrinsic capacity to fight cancer such as T cells or natural killer (NK) cells, is a promising treatment option for many patients.
However, infusion of cells from an unrelated donor can lead to rejection responses by the patient’s immune system, similar to how transplanted organs are often rejected.
Importantly, if the infused cells are quickly destroyed by the patient’s immune system, the transferred cells cannot effectively fight the patient’s cancer, thereby limiting treatment efficacy.
The overall objective of the SYNKIT action is to address this limitation of current immunotherapies by applying synthetic biology in the form of genetic engineering with the goal to reduce rejection of transferred cells. Reduced rejection will result in extended persistence of the infused cells in the patient and by this will optimise the anti-cancer function of cell therapy.
Thus, successful completion of SYNKIT will pave the way for the development of next-generation immunotherapy to combat cancer more effectively.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Within the SYNKIT action, we have identified a promising novel approach to reduce rejection of allogeneic immune cells by limiting adhesion with means of genetic engineering. We have demonstrated that genetic deletion of adhesion ligands restricts the formation of immune synapses between transferred cell products and the host’s immune cells. This innovative approach has been validated in both NK and T cells and has been in-depth characterised in a broad range of cell culture settings including newly established methodologies. Furthermore, analysis of numerous different samples highlighted the potential for universal application to many patients. The concept developed in the frame of SYNKIT has been successfully employed in a preclinical model of cancer immunotherapy and, with support from scientific and industrial partners, has been transferred to a cutting-edge platform for next-generation immunotherapy using induced pluripotent stem cells as source for cell products. IPR filing is in progress and further preclinical assessment is ongoing with clinical exploitation in preparation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

State-of-the art strategies to limit rejection by the patient’s immune system and extend persistence of the transferred cells mainly focus on rejection by T cells of the patient. However, modifications to reduce T cell-mediated rejection such as genetic deletion of the B2M gene render transferred cells highly susceptible to attack by the patient’s NK cells. Within the SYNKIT action, we have built on and extended previous strategies and developed as well as validated a novel approach that averts NK cell-driven rejection of allogeneic immune cells even if the B2M gene is absent.
Improving the therapeutic value of current immunotherapy and paving the way for the development of next-generation therapy strategies hold considerable translational value for a large population of cancer patients.

Summary of the SYNKIT action. (A) Conceptual illustration. (B) Schematic side-by-side comparison.