Edited CAR effector cell therapy targeting adaptive resistance to therapeutic Menin-KMT2A chromatin complex disruption in leukemia (12)

• Subject Area: Immunology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318346496

Following our discovery that the Menin-KMT2A interaction is a key therapeutic target in NPM1mut AML, four different Menin inhibitors have shown promising efficacy in early clinical trials, but menin inhibitor resistance has already emerged as a significant clinical challenge. During the second funding period, we found that Menin inhibition upregulates C-type lectin-like receptor CLEC12A on AML blasts, thereby enhancing the efficacy of CLEC12A-directed CAR-T cells. In this funding period, we will assess potential immune escape mechanisms aiming at overcoming menin inhibitor drug resistance by engineering optimized CAR-T cells. Therefore, we have developed an adaptive, non-genetic NPM1mut AML model of Menin inhibitor drug resistance, characterized by reactivation of stem-like genes but maintained CLEC12A expression that will be compared with Menin inhibitor-resistant patient samples. Detailed epigenetic and transcriptional characterization of the resistant cells will be integrated with current CAR-T constructs to understand potential mechanisms of immune escape. This knowledge will be applied to engineer novel nanobody-based CAR-T cells targeting CLEC12A and use CRISPR/Cas9 and base editing to overcome immune suppression. Optimized CAR-T cells will be assessed in vitro with all different menin inhibitors. For in vivo assessment of the combinatorial therapy concept, we will use patient-derived xenograft models from NPM1m AML patients with primary Menin inhibitor resistance. This project will provide key insights into understanding and overcoming Menin inhibitor-induced resistance mechanisms through co-treatment concepts with edited CAR immune cell preparations.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1292: Targeting convergent mechanisms of inefficient immunity in tumors and chronic infections
• Applicant Institution: Johannes Gutenberg-Universität Mainz
• Project Heads: Professorin Dr. Simone Fulda, until 12/2021; Professor Dr. Michael Kühn; Professorin Dr. Evelyn Ullrich