Augmenting the Anti-Tumor Immunity of CAR Armed Cytokine-Induced Memory-Like Natural Killer Cells by Novel CD73-directed Checkpoint Immunocytokines in AML

• Applicant: Dr. Stephanie Sendker
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539544097

Despite recent advances in risk-adapted therapy and prognosis, acute myeloid leukemia (AML) is still associated with a devastating prognosis, especially in relapsed and refractory disease. Successful treatment requires effective eradication of resistant leukemic blasts, residing in a hijacked environment. Harnessing the body´s own immunity and redirecting it against leukemia using immunotherapeutic strategies has dawned a new era in oncology. In recent years, various immunotherapeutic approaches have been attempted. Among these, natural killer (NK) cells have proven to be a particularly effective and safe immunotherapeutic weapon due to their innate toxicity against malignant cells. However, the clinical success of these powerful effector cells is hampered by i) limited in-vivo persistence, ii) ingenious strategies of malignant blasts to evade immunity, and iii) lack of antigen specific recognition allowing therapeutic escape of AML blast. Therefore, novel immunotherapeutic approaches are needed to reconstitute anti-leukemia immunity and specifically direct activated NK cells against malignant blasts. This project aims to exploit the immunogenic power of allogeneic NK cells in AML by combining three promising immunotherapeutic concepts: i) Cytokine-based strategies, namely i.a) Cytokine-induced memory-like (CIML) NK cells, showing prolonged in-vivo persistence and enhanced immunity; i.b) NK cell stimulating immunocytokines, complexing the CD16/FcγRIII killer engaging domain with an IL15/IL15Rα-sushi (IL15RαSu) moiety. ii) Targeted checkpoint inhibition of the ectoenzyme 5´-nucleotidase (5´NTE)/CD73 that serves as an excellent target to restore NK cell toxicity by abrogating the adenosine-mediated immunosuppression while simultaneously redirecting the unleashed immunity against malignant blasts, given its favorable expression profile in AML. iii) Enhancing CIML NK cells with a chimeric antigen receptor (CAR) directed against C-type lectin-like molecule-1 (CLL1/CD371), which is one of the most promising targets to increase tumor-antigen specificity while reducing off-tumor toxicity given its high expression in AML but not on healthy hematopoietic cells. Therefore, my project aims to genetically engineer i) CIML NK cells to secrete self-stimulating IL15RαSu immunocytokines, fused to ii) CD73 directed checkpoint inhibitor to revert immunosuppression into NK cell activation. Binding of the immunocytokine-checkpoint inhibitors concomitantly provides local IL15 immune stimulation for immune effector cells leading to amplified anti-tumor immune response in the leukemic environment. These enhanced CIML NK cells will be armed with CLL1-specific CAR constructs iii) to specifically redirect their unleashed immunogenic power against leukemic blasts. Given the logical structure of these checkpoint immunocytokine enhanced CIML NK CARs, my project provides a perspective for future therapeutic concepts not only for AML but also potentially other malignancies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Rizwan Romee