Project 2: Memory-like NK cell therapy for AML relapsed after allogenic transplant

Project 2 Co-Leaders:

Todd Fehniger, MD, PhD (WashU)

Amanda Cashen, MD (WashU)

Immunotherapy is a type of cancer treatment that alters components of the immune system to increase their response to cancer.  This project seeks to develop new forms of immunotherapy for a difficult-to-treat blood cancer, acute myeloid leukemia (AML). For patients with AML, standard treatments include chemotherapy, and if there is a higher risk of relapse,  hematopoietic stem cell transplant (HCT).  If AML relapses after HCT there are few standard treatment options that work, and hence, a great need to develop new treatments.

This project addresses this unmet clinical need by using an immune cell, the natural killer (NK) cell, to treat AML.  In a clinical trial, patients who have AML that relapsed after HCT receive ‘super charged’ memory-like NK cells that have been programmed via protein hormones (cytokines) for improved anti-tumor attack.  NK cells collected from the original HCT donor will be used to generate the therapeutic memory-like NK cells, which are activated by interleukins 12, 15, and 18 overnight, prior to infusion into the patient. Patients first receive mild chemotherapy to make space within the patient for the cells to expand, persist, and fight the leukemia. As part of this study, the patients’ samples will be examined for the quality and quantity of the transferred NK cells.  Leukemia cells will be tested for properties that result in resistance to NK cells.

In a second part of the project, a pre-clinical study will test recently identified approaches to further improve memory-like NK cell responses to cancer.  These include blocking an inhibitory or “off” signal to the NK cell delivered by the cancer cells, as well as engineering memory-like NK cells to express chimeric antigen receptors that help them “see” and therefore attack cancer cells more effectively.  This part of the project will lead to new clinical trial ideas to test improved versions of memory-like NK cells in combination with NK cell-checkpoint blockade.

Collectively, this project will test a promising cellular therapy for leukemia in a clinical trial, and develop new ways to further increase the activity of NK cells against cancers.