Study protocol for a phase II, multicentre, prospective, non-randomised clinical trial to assess the safety and efficacy of infusing allogeneic activated and expanded natural killer cells as consolidation therapy for paediatric acute myeloblastic leukaemia

Abstract

IntroductionAcute myeloblastic leukaemia (AML) constitutes the second most common haematological malignancy in the paediatric population. Current treatment regimens are based on the administration of polychemotherapy, combining high doses of cytarabine with anthracyclines and topoisomerase inhibitors. Allogeneic haematopoietic stem cell transplantation (HSCT) is an option for high-risk patients with AML (and for intermediate-risk patients if a sibling donor is available). With this strategy, AML survival has increased substantially; however, it has remained stagnant at approximately 60%, with relapse being the principal culprit. The predominant role of the immune system and natural killer (NK) cells in controlling paediatric AML has gained importance within the context of HSCT. In this protocol, we propose incorporating this cell therapy as an adjuvant treatment through the infusion of activated and expanded haploidentical NK (NKAE) cells in paediatric patients with AML who are in cytological remission after completing consolidation therapy, and with no indication for HSCT.Methods and analysisPatients up to 30 years of age, diagnosed with AML, in their first cytological remission, who have completed both the induction and the consolidation phases of chemotherapy and do not meet the criteria for allogeneic HSCT are eligible. The patients will receive two doses of NKAE cells once a week, using a GMP K562-mbIL15-41BBL stimulus from a haploidentical donor and interleukin 2 subcutaneously. The patients will then be followed up for 36 months to assess the primary endpoint, which is the probability of relapse after NK cell infusion.Ethics and disseminationThis clinical trial was approved by the Clinical Research Ethics Committee of La Paz University Hospital and The Spanish Agency of Medicines and Medical Devices. Findings will be disseminated through peer-reviewed publications, conference presentations and community reporting.Trial registration numberEudraCT code: 2015-001901-15, ClinicalTrials.gov Identifier:NCT02763475.

Clinical grade production of IL‐15 stimulated NK cells for early infusion in adult AML patients undergoing haploidentical stem cell transplantation with post‐transplant cyclophosphamide

“…Although the clinical impact of NK cell infusions remains uncertain, in the last years, several trials have obtained promising results in adult 5,6,9,12–14,21–30 and pediatric 28,31–36 hematologic patients using haploidentical NK cells. These exploratory trials have studied their use after chemotherapy in acute leukemia, 9,17,21,25,26,28,31,33,36 lymphoma, 24,30 and myeloma, 29 demonstrating them to be safe.…”

From CAR-T Cells to CAR-NK Cells: A Developing Immunotherapy Method for Hematological Malignancies

“…Besides, adoptive NK cell transfer either alone or combined with chemotherapy could also be used as a post-CR consolidation strategy in AML (108,109). A phase II trial that transfusing NK cells as a consolidation therapy in pediatric patients with AML has been conducted, and the result is still awaited (110). Additionally, one study also suggested that infusing NK cells could also consolidate incomplete engraftment in patients after haploidentical HSCT (19).…”

Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox

“…In another phase II clinical trial, although NK cells were activated and expanded by K562-MB15-41BBL feeder cells before infusion, the efficacy assessment was limited by the number of participants (only 7 patients) [ 14 ]. Encouragingly, a prospective phase II clinical trial involving up to 6 institutions is currently being prepared to assess the clinical efficacy of administrating activated and expanded NK cells for AML [ 205 ]. Taken together, with proper processing, adoptive NK cell-based immunotherapy is a safe and promising strategy to complement current polychemotherapy-based leukemia treatment options.…”