Kurzfassung

Individualized CAR-T therapy has advanced as a powerful immunotherapy for leukemia and has high potential to revolutionize treatment of many cancers that currently lack options for sustained and durable remission. However, redirection of CAR expressing T lymphocytes is limited to autologous T cells from patients, and their biological “fitness” depends on e.g. pretreatment and age of the patient resulting in poor standardization of a defined CAR T cell product. Alternative use of allogeneic T...Individualized CAR-T therapy has advanced as a powerful immunotherapy for leukemia and has high potential to revolutionize treatment of many cancers that currently lack options for sustained and durable remission. However, redirection of CAR expressing T lymphocytes is limited to autologous T cells from patients, and their biological “fitness” depends on e.g. pretreatment and age of the patient resulting in poor standardization of a defined CAR T cell product. Alternative use of allogeneic T cells from a healthy donor carries a high risk of inducing graft-vs-host disease and is therefore not yet clinically feasible. Moreover, T CAR therapy is commonly associated with severe adverse effects such as e.g. the cytokine release syndrome. Since allogeneic natural killer (NK) cells do not induce alloreactivity in patients and have been shown to be a promising alternative source for CAR therapy, this project aims to generate an “off-the-shelf” CAR NK cell product using the FDA-approved NK cell line NK92 and induced pluripotent stem cell-NK cells, respectively. We focus on NKp30-based 2nd generation CARs previously shown by us and others to elicit potent anti-tumor responses in B7H6 (NKp30 ligand) positive tumors which can be further sustained by introducing single amino acid substitutions within the NKp30-B7H6 interface. B7H6 is almost exclusively expressed on tumor but not on healthy tissues. Moreover, as our previous studies further revealed that a significant subset of acute myeloid leukemia (AML) samples expresses B7H6 as a promising CAR target, we will evaluate the therapeutic efficacy of NKp30 CAR NK therapy to AML in vitro and in vivo using an established minimal residual disease defined AML-xenograft NSG-mouse model.» weiterlesen» einklappen