Phase I / II study on infusion of alloreactive or stimulated Natural Killer cells with IL-15 ex vivo after haploidentical transplantation of hematopoietic progenitors in pediatric patients with hematologic malignancies (PHINK
Haploidentical hematopoietic stem cell transplantation (haploTPH) constitutes a highly complex but effective procedure for some hematologic malignancies high-risk pediatric patients in the absence of an identical HLA donor. Relapse Post-transplant leukemia is the main problem for survival. Just like reported different expert groups on haploTPH in adults and children, there is a determining role of Natural Killer (NK) cells in haploTPH as inducers powerful graft-versus-leukemia (EIcL) effect. The presence of NK cells allo-reactive is correlated with a lower relapse rate, in addition to favoring the graft, decrease graft versus recipient disease (GVHD) and decrease viral infections. This only occurs in half of the donor-recipient pairs, so that, in its absence, it is necessary to develop other strategies for activating the NK cells. In this sense, the investigational group has extensive experience in research translational with NK cells and is a pioneer in infusing ex vivo activated NK cells with IL-15. The investigators propose a phase I / II clinical trial with dose escalation, multicenter, framed in the Spanish Group of Hematopoietic Transplantation / Marrow Transplant Bone in Children (GETH / GETMON), to determine the safety and efficacy of a post-haploTPH IL-15 alloreactive / stimulated NK cell infusion in children with malignant blood diseases. The investigators will monitor immune reconstitution, chimerism, Post-transplantation NK cell expansion, phenotype, and function. Secondarily evaluate the effectiveness of therapy on the incidence of graft failure; EICR; viral reactivations; transplant-related mortality; and relapse of leukemia.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
When patient and donor are KIR-HLA match, the patient submits all HLA class I molecules, or in the absence of any, your donor does not have this molecule, or having it lacks the corresponding KIR receiver. For more information detailed information on the product under investigation, reference is made to the Dossier of the Research Product (IMPD): PEI 09-008
When the patient lacks the HLA class I molecule and his donor has this molecule and also the donor NK cells have the KIR receptor that recognizes the absence of the corresponding HLA class I ligand
Hospital Clínico Universitario de Santiago
Santiago de Compostela, A Coruña, Spain
Hospital Universitario Central de Asturias
Oviedo, Principality of Asturias, Spain
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain
Dose-limiting toxicity (TLD)
To determine dose-limiting toxicity (TLD) of a single infusion of aloreactive NK cells or ex vivo IL-15-stimulated NK cells after haploTPH in pediatric patients with high-risk leukemias.
Time frame: 52 weeks
Maximum tolerated dose (MTD)
To determine maximum tolerated dose (MTD) of a single infusion of aloreactive NK cells or ex vivo IL-15-stimulated NK cells after haploTPH in pediatric patients with high-risk leukemias.
Time frame: 52 weeks
Efficacy of post haploTPH NK cell therapy
The efficacy of post haploTPH NK cell therapy will be determined, comparing it with the historical cohort recently reported by GETH/GETMON in the incidence of graft failure, acute/chronic GVHD, viral reactivations (CMV, EBV, HHV-6, adenovirus, BKV), transplant-related mortality (TRM), and leukemia relapse.
Time frame: Week 52
Clinical evolution of patients
The clinical course of patients will be compared based on the dose of infused NK cells, KIR match vs. KIR mismatch NK cells, expansion, chimerism, and phenotypic and functional characteristics of the infused NK cells, and the speed and characteristics of immune reconstitution post haploTPH.
Time frame: Week 52
Monitor immune reconstitution and characterize NK cells
Immune reconstitution will be monitored by quantifying immunoglobulins at different times, and characterizing NK cells in patients, at a phenotypic and functional level, for 1 year after haploTPH
Time frame: Week 52
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Hospital General Universitario Gregorio Marañón
Madrid, Spain
Hospital Infantil Universitario Niño Jeús
Madrid, Spain
Hospital Universitario La Paz
Madrid, Spain
Hospital Regional Universitario de Málaga (Carlos de Haya)
Málaga, Spain
Hospital Clínico Universitario Virgen de la Arrixaca
Murcia, Spain
Hospital Universitario Virgen del Rocío
Seville, Spain
Hospital Universitario La Fe
Valencia, Spain