Safety Analysis of Ex Vivo -Expanded NK and NK-Like T Cells Administered to Cancer Patients: a Phase I Clinical Study

Abstract

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

“…There are several phase I clinical trials using either KIR-HLA mismatch NK cells 115 or expanded allogenic NK cells. 116 These trials have shown so far that NK cell immunotherapy is safe, where no side effects were observed after the infusion of high or low doses of NK cells.…”

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

“…They are further attractive, because their numbers can be expanded significantly ex vivo and the expanded cells remain highly active for ADCC after recruitment through CD16-engaging abs and ab-derived agents [156][157][158]. In our team, we have been able to expand the number of NK-cells from peripheral blood of healthy donors and from cryo-preserved leukapheresis samples by several hundred-fold through culture for 21 days in the presence of IL-2 [159].…”

Kill the Killers: terapia con células Natural Killer en pacientes pediátricos con cáncer refractario

“…Con esta estrategia perseguimos conseguir un efecto inmunológico mediado por las células NK, a través de la reconstitución inmune y del «boost» post trasplante de células NK estimuladas ex vivo con IL15, de manera similar al objetivado en hemopatías malignas 26,27 . Sin embargo, y en vista de los resultados obtenidos con este trabajo, planteamos la inmunoterapia con células NK-IL15 como un procedimiento muy alentador en el tratamiento de tumores refractarios, incluso fuera del trasplante alogénico de donante haploidéntico [28][29][30][31][32][33][34][35] .…”