CIML NK cell immunotherapy for relapse after haploidentical hematopoietic cell transplantation
Rizwan Romee
MDDana-Farber Cancer Institute
Project Term: July 1, 2019 - June 30, 2022
Relapse remains major risk after hematopoietic cell transplantation, with limited effective treatment options and extremely poor prognosis. We described human cytokine induced memory-like (CIML) NK cells with enhanced anti-leukemia activity. CIML NK cells were safe and with promising clinical activity in our phase 1 clinical trial. Here we propose to test the safety and potential efficacy of CIML NK cells in patients with myeloid malignancies relapsed after haploidentical donor transplantation.
Acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) are some of the commonest blood cancers in adult patient population, less than half of whom are cured with current treatment approaches. Hematopoietic stem cell transplantation (HSCT) is potentially curative for these patients but its utilization had been limited by donor availability. Recent advances in HLA-haploidentical (‘half-matched’) transplantation help ensure donor availability in almost all patients. However, disease relapse remains an unmet challenge, with very limited survival after usual treatment including taper of immunosuppressive medications, chemotherapy and/or donor lymphocyte infusions. Natural Killer (NK) cells are a type of innate immune cells with intrinsic anti-tumor activity, but harnessing them clinically has been challenging. We described cytokine-induced memory-like (CIML) NK cells with superior anti-leukemia activity and persistence. In our recent first-in-human early phase non-transplant clinical trial, infusion of CIML NK cells from haploidentical donors in patients with advanced relapsed/refractory AML was safe and demonstrated promising clinical activity with 6 out of 11 evaluable patients achieving a complete remission. We now propose to evaluate the safety and efficacy of CIML NK cell therapy in the transplant context, in a phase 1 clinical trial for patients with AML, MDS and MPN relapsed after haploidentical stem cell transplantation, where a donor-derived bone marrow environment permits extended activity and survival of the infused cells. In correlative studies, we will evaluate CIML NK cell expansion, survival, activation, and function in the treated patients, and examine potential mechanisms of response and resistance to CIML NK therapy. If found safe and with an efficacy signal in this early phase clinical trial we intend to test CIML NK cells in a larger randomized clinical trial in near future. This approach has a potential to become a viable treatment option for patients who relapse after haploidentical stem cell transplantation. These patients otherwise have an extremely poor with the current standard of care treatment options.