Development of long-lived tumor homing NK cells to induce durable leukemia remission: exploration of novel chimeric cytokine signaling receptors and JAK-STAT signaling CARs

Adoptive infusion of natural killer (NK) cells can induce remission in 30-50% of patients with advanced acute myeloid leukemia (AML).

Poor persistence and tumor homing of the NK cells have been identified as the main hurdles limiting their full potential.

We have generated strong preliminary data indicating that NK cells can be redirected to the bone marrow (BM) via modulation of the homing molecules CXCR4 and PSGL1 while introduction of our novel chimeric cytokine-signaling receptors can support their persistence. The purpose of this proposal is to gain new biological insights while developing new treatment strategies for AML.

The goal is to establish proof-of-concept for utilizing gene engineered NK cells to induce durable leukemia responses via improved tumor homing and prolonged persistence.

Within the project, we will also explore the potential of chimeric antigen receptors with integrated cytokine signaling. The project will be conducted in my lab using genetic engineering, immunology assays and animal models. I will be the project leader supporting the work by one PhD student and two post-docs on this project.

The two distinct types of persistence receptors will be explored in parallel the first 3-years, while final proof-of-concept will be generated the last 2-years. Positive results will be translated into clinical trials headed by me at Karolinska University Hospital. All methods, material and ethical approvals are available, why feasibility is deemed to be high.