Bioengineering of human NK cells for combined immunotherapy

• Applicant: Meike Kaulfuß
• Subject Area: Immunology ; Virology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415801544

The treatment options of cancer patients have changed fundamentally during the last five years due to new immunotherapeutic approaches. The use of genetically modified T cells expressing chimeric antigen receptors (CARs) directed against the antigen CD19, which is present on neoplastic cells, reach a complete remission rate of 50-90% in patients with refractory or recurrent hematological cancers such as acute lymphoblastic leukemia, classical Hodgkin's lymphoma, or diffuse large cell B-cell lymphomas. Despite the promising initial successes and the approval of two immune cell products by the US Food and Drug Administration (FDA), there is still an urgent need for further improvement. Thus, there are some life-threatening undesirable effects such as the cytokine release syndrome and severe neurotoxicities. Antigen losses with consecutive treatment failure are observed in a large part of the treated patients and in metastasized non-hematological cancers a similar success as in hematological diseases has not been achieved so far, partly due to the lack of suitable specific singular antigens.To further improve immunotherapy, we will therefore evaluate the use of genetically modified natural killer cells. Natural killer cells are known to have antigen-independent intrinsic anti-tumor activity. In adoptive transfer of NK cells in clinical trials as part of haploid identical hematologic stem cell transplantation, they did not show an increased risk of graft-versus-host disease, cytokine release syndrome or increased neurotoxicity and thus appear to have a more favorable side-effect profile. Therefore, after successful generation of mono- and bi-specific anti-CD19 and / or anti-CD20 CARs, a direct comparison of the cytotoxic activity of CAR-NK and CAR-T cells against antigen-expressing tumor cells will be made in vitro. By CRISPR-mediated knockout of the inhibitory receptor NKG2A in sense of a checkpoint inhibition, the cytotoxicity should be further improved. Subsequently, the anti-tumor activity in mice with human immune system (HIS mice) will be characterized in vivo against Epstein-Barr virus-induced autologous human tumors.Due to NK cells inherent anti-tumor activity compared to single-specific CAR-T cells, combination with NKG2A checkpoint inhibition, as well as directed co-targeting of CD19 and CD20 to prevent antigen loss, we expect a significant improvement of therapeutic potential of genetically modified immune cells in the fight against cancer.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Christian Münz