Memory-Like Natural Killer Cells for Patients With Advanced AML and MDS

Rizwan Romee, MD
Published: Monday, Oct 26, 2015
Siteman Cancer CenterCatherine M. Diefenbach, MD
Rizwan Romee, MD
Medical Oncologist
Siteman Cancer Center
Assistant Professor of Medicine
Washington University School of Medicine
St. Louis, MO
Rizwan Romee, MD
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are the two most common hematologic malignancies of the myeloid lineage origin and both are more common in older patients. The median age of diagnosis for AML is around 67 years and has an estimated prevalence of 3.8 cases per 100,000. Unfortunately, less than half of AML patients are cured with current treatment approaches. The prognosis is particularly poor in older patients (≥60 years), in whom the success of achieving complete remission are significantly lower than younger patients and the long-term disease free-survival is often measured in single digits if patients are not eligible for stem cell transplantation. Furthermore, patients who are unable to achieve complete remission and or relapse after two or more chemotherapeutic regimens have extremely dismal outcomes, even with stem cell transplantation.

MDS is also more common in older patients and their long-term curative options are also limited if they are not eligible for stem cell transplantation. MDS patients without treatment often progress to acute myeloid leukemia. Hypomethylating agents, including azacytidine and decitabine, are the only class of medications that have demonstrated some clinical efficacy in these patients. However, patients with MDS who have failed and/or progressed while on hypomethylating agents have very limited treatment options.

Even with stem cell transplantation the outcomes are suboptimal in MDS patients with pretransplant high blast counts, underscoring an urgent need for developing more innovative treatment options for these patients.

Natural killer (NK) cells are innate immune lymphocytes important for host defense against pathogens and surveillance against malignant transformation. Early phase studies have demonstrated that allogeneic NK cells are a promising cellular therapy for leukemia. However, limited persistence and expansion of the adoptively transferred NK cells seen in previously reported studies remain some of the major limitations of the currently used strategies for NK cell–based immunotherapy protocols.

Recent work in the NK cell field has challenged their classification as members of the innate immune system, identifying memory-like properties of NK cells. This has included the identification of human cytokine-induced memory-like (CIML) NK cells by our group at Washington University School of Medicine, following preactivation with IL-12, IL-15, and IL-18. Human CIML NK cells exhibit enhanced cytokine and cytotoxic responses against myeloid leukemia target cells and they retain this enhanced functionality following transfer into immunodeficient NOD-SCID-gc-/- mice. Based on their enhanced antileukemia responses and ability to proliferate and expand after adoptive transfer, CIML NK cells are an attractive option to explore in relapsed/refractory AML and in MDS patients who have failed and/or progressed on hypomethylating agents.

We are currently enrolling patients on a firstin- human phase I study using CIML NK cells for advanced MDS and AML patients.

Eligibility: Patients (≥ 18 years) with one of the following diagnosis:

1. Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR.

2. High-risk AML in complete remission (CR) and has either refused hematopoietic stem cell transplantation or is currently not eligible for hematopoietic stem cell transplantation or for whom hematopoietic stem cell transplantation is being reserved for later relapse.

3. MDS with excess blasts (>5%) and failed/progressed with the hypomethylating therapy.

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