The long term goal of this project is to translate novel findings in the field of innate immunity into early phase immunotherapy clinical trials for patients with hematologic malignancies. In this proposal we focus on acute myeloid leukemia (AML), an aggressive cancer of developing myeloid cells that has a poor prognosis, with <30% of patients treated with standard therapy achieving long-term disease-free survival. While allogeneic hematopoietic cell transplantation (HCT) is a standard treatment that is potentially curative for some patients with AML, this therapy is associated with significant morbidity (graft versus host disease and infection) and treatment-related mortality. This limits HCT applicability and overall effectiveness in this disease of older individuals. One promising strategy that preserves the anti-leukemia effector function against AML, without the morbidity and mortality of HCT, is the adoptive transfer of allogeneic lymphocytes. Natural killer (NK) cells are innate lymphoid cells that are specialized to eliminate malignantly transformed target cells. Clinical studies for AML patients using HLA-haploidentical allogeneic HCT have shown that the reactivity of donor NK cells against the patients' leukemia predicts for long-term disease-free survival. Adoptive immunotherapy with enriched allogeneic NK cell products administered to patients with active AML have resulted in complete remissions, although these are achieved in a minority of patients and are of limited duration. We hypothesize that enhancing NK cell recognition of, and effector function against, AML blasts will result in improved clinical outcomes following adoptive NK cell therapy. Recently, paradigm shifting studies have shown that NK cells exhibit immune memory, a property previously attributed only to adaptive T and B lymphocytes. We have established that human NK cells exhibit innate memory following a brief combined stimulation with interleukins (IL)-12, -15, and -18. Preliminary data demonstrates that memory-like NK cells exhibit significantly enhanced AML recognition, functionality, longevity, and proliferative potential compared to naive or control NK cells. Recent preliminary data also shows that administration of allogeneic memory-like NK cells is safe, feasible, and results in clinical responses in AML patients. Thus, we hypothesize that allogeneic memory-like NK cells administered as adoptive immunotherapy for patients with AML will exhibit potent anti-leukemia responses. In this proposal, we will 1) test the safety and efficacy of allogeneic memory-like NK cell adoptive immunotherapy in a first-in-human phase 1/2 clinical trial for patients with relapsed AML, 2) define memory-like NK cell correlates of clinical response, and elucidate key mechanisms important for memory-like NK cell anti-AML responses, and 3) define the importance of NKG2A as a memory-like NK cell checkpoint, and elucidate mechanisms of AML resistance to memory-like NK cell therapy.

Public Health Relevance

Natural killer (NK) cells are immune cells that mediate anti-cancer immune responses. Our research will complete a first-in-human phase 1/2 clinical trial for patients with acute myeloid leukemia, testing a novel approach to enhance adoptive NK cell therapy through the differentiation of memory-like NK cells. Additional goals of this research are to identify new ways to augment memory-like NK cell responses to cancer cells. We expect that this research will lead to new immunotherapy strategies to treat patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA205239-02
Application #
9542272
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2017-08-09
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Romee, Rizwan; Cooley, Sarah; Berrien-Elliott, Melissa M et al. (2018) First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 131:2515-2527
Fehniger, Todd A; Miller, Jeffrey S; Stuart, Robert K et al. (2018) A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia. Biol Blood Marrow Transplant 24:1581-1589
Cooper, Megan A; Fehniger, Todd A; Colonna, Marco (2018) Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Vaccination Strategies Based on NK Cell and ILC Memory. Cold Spring Harb Perspect Biol 10:
Bansal, Dhruv; Vij, Kiran; Chang, Gue Su et al. (2018) Lenalidomide results in a durable complete remission in acute myeloid leukemia accompanied by persistence of somatic mutations and a T-cell infiltrate in the bone marrow. Haematologica 103:e270-e273
Wagner, Julia A; Rosario, Maximillian; Romee, Rizwan et al. (2017) CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. J Clin Invest 127:4042-4058