Memory-like natural killer cells and venetoclax to eradicate measurable residual disease in AML
Maximilian Stahl
MDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
This proposal is to conduct a phase I (early phase) clinical trial to test whether the combination of the approved targeted therapy venetoclax with memory-like Natural Killer (NK) cells is safe and active in patients with acute myeloid leukemia (AML). Based on laboratory research at Dana-Farber Cancer Institute, we believe that the addition of memory-like NK cells obtained from an haploidentical (‘half matched’) donor will be able to eradicate residual leukemia cells left over after prior venetoclax treatment and hence prevent a future relapse of the disease. A total of 10 patients will be treated with two different doses of NK cells and a constant dose of venetoclax. We also plan scientific studies on patient samples to learn more about the function of NK cells when combined with venetoclax, evaluate for clearance of residual leukemia cells with this combination therapy and explore potential resistance mechanisms.
Venetoclax, a targeted therapy inhibiting a protein called bcl-2, has become the new standard of care for patients with acute myeloid leukemia (AML) who are older than 75 years old and considered not healthy enough to receive intensive chemotherapy. While most AML patients initially respond to venetoclax based therapy, almost all patients eventually develop resistance to venetoclax and subsequently suffer from a relapse of their disease. Consequently, the average survival time with venetoclax based therapy is only about 14 months. This is because venetoclax is not able to eliminate all leukemia cells and leaves very small amounts of disease, so called measurable residual disease (MRD) behind. Hence, there is an urgent need to develop improved therapeutic approaches focused on the elimination of MRD with the goal to prevent disease relapse. Based on basic laboratory research at Dana-Farber Cancer Institute (DFCI), we believe that the addition of so-called cytokine induced memory like (CIML) natural killer (NK) cells obtained from a half-matched donor will be able to eradicate MRD and hence prevent a relapse of the disease. Investigators at DFCI have been intimately involved in the development of venetoclax (Tony Letai Lab) and the first study showing promising responses with CIML NK cells in AML was conducted at DFCI (Rizwan Romee Lab). Hence, DFCI offers the ideal environment to study the combination of both approaches in a clinical trial and to conduct basic scientific studies in the laboratory to understand predictors of response and development of resistance.
We propose to conduct a clinical trial testing whether CIML NK cells plus venetoclax are safe in AML patients who have achieved a response to initial venetoclax based therapy but still have evidence of MRD and hence are at high risk for relapse. Two doses of CIML NK cells in combination with venetoclax will be studied. The study will enroll a total of 10 patients with 5 patients at each dose. After NK cell infusion, patients will receive low dose interleukin-2 injections to help with for NK cell expansion and will take venetoclax daily for 14 days. All patients will have a bone marrow biopsy performed prior to and after completion of treatment to assess the response to CIML NK cells + venetoclax. We will use blood and bone marrow samples obtained from patients on the trial to measure the function of infused NK cells and evaluate MRD clearance. We will also explore potential resistance mechanisms to combination therapy including a decreased readiness to undergo programmed cell death in surviving AML blasts and changes in NK cell characteristics and the number of other immune cells in the bone marrow microenvironment. Our hypothesis is that CIML NK cells will function well and that the combination of CIML NK cells with venetoclax will lead to potent elimination of MRD leading to a reduction of the relapse risk for these patients.