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RP11

Miriam Frech / Andreas Burchert: Overcoming immunosuppressive mechanisms in leukemia

AIM: Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are heterogeneous diseases, in which immune evasion mechanisms of the tumor cells and the TME play a crucial role in prognosis and therapy response. Hence, it is important to identify molecular mechanisms and key factors involved in these immunoregulatory mechanisms to improve the therapy and prognosis of patients. Within this project (i) the oncoprotein Ski and Ski-regulated immune factors will be analyzed and targeted in a KMT2A-MLLT3/NRasG12D-based AML mouse model aiming to overcome Ski-mediated immune evasion (Frech). In CML (ii) the immunological control of treatment-free remission (TFR) which is a rare and mechanistically poorly understood condition in the context of tyrosine kinase inhibitor (TKI) treatment will be analyzed using patient samples from the ENDURE clinical trial (Burchert).

STATE of the ART: AML patients with KMT2A rearrangements (KMT2Ar) have an intermediate to adverse risk and KMT2Ar acute leukemia patients are often prone to resistance and relapses following standard treatments. The leukemic secretome establishes a tumor-promoting microenvironment and promotes resistance and immune evasion. In CML an Insufficient immune surveillance of tumor cells is also observed in patients who are treated with BCR::ABL-specific TKI. Although TKI therapy can restore changes in the immune cell repertoire during remission this is not sufficient to regain immune control, because most patients will require lifelong TKI therapy to stay in remission. Of note, a part of CML patients will become eligible to discontinue TKI treatment and remain in so-called therapy-free remission (TFR; approx. 20%). Understanding the underlying immunological mechanisms for TFR will help to develop therapies to promote anti-tumor immunity and TFR.