Autologous stem cell transplant recipients tolerate haploidentical related-donor natural killer cell-enriched infusions
ABSTRACT BACKGROUND: In the setting of allogeneic stem cell transplantation (SCT), infusing natural killer (NK) cells from a major histocompatibility complex (MHC)-mismatched donor can mediate an antileukemic effect. The graft-versus-tumor effect after autologous stem cell transplantation (ASCT) may result in less disease relapse. STUDY DESIGN AND METHODS: We performed a Phase I clinical trial to assess the safety and feasibility of infusing distantly processed donor NK-enriched mononuclear cell (NK-MNC) infusions from a MHC haplotype-mismatched (haploidentical) donor to patients who recently underwent ASCT for a hematologic malignancy. On Day 1, peripheral blood MNCs were obtained by steady-state leukapheresis and sent from Boston to the Production Assistance for Cellular Therapies (PACT) facility at the University of Minnesota, where immunomagnetic depletion of CD3 cells was performed on Day 2. NK-MNC products were then returned to Boston on Day 2 for infusion on Day 3. Toxicity, cellular product characteristics, and logistic events were monitored. RESULTS: At a median of 90 days (range, 49-191 days) after ASCT, 13 patients were treated with escalating doses of NK-MNCs per kilogram from 10(5) to 2 × 10(7) . Adverse effects included Grade 2 rigors and muscle aches, but no Grade 3 or 4 events and no graft-versus-host disease or marrow suppression. One air courier delay occurred. NK-MNC products were viable with cytotoxic activity after transport. CONCLUSION: CD3-depleted, MHC-mismatched allogeneic NK-MNC infusions can be safely and feasibly administered to patients after ASCT after distant processing and transport, justifying further development of this approach.
- Transfusion 02/2013; 53(2):245-8. DOI:10.1111/trf.12091 · 3.57 Impact Factor
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ABSTRACT: Although T-lymphocytes have received most of the attention in immunotherapy trials, new discoveries around natural killer (NK) cells suggest that they also should be suitable effector cells for cellular therapy of cancer. In addition to direct cytotoxicity, NK cells produce an array of immune-active cytokines, among them interferons and granulocyte-macrophage colony-stimulating factor, which places them at the crossroads of innate and adaptive immunity. They also augment monoclonal antibody activity through antibody-mediated cellular cytotoxicity and can be transfected with chimeric antigen receptors. One of the stumbling blocks for NK cell-based therapies has been the inability to predictably obtain and expand larger numbers from donors, but also to achieve sufficiently high transfection efficiency of target genes. The first clinical trials with NK cells suggest some benefit, but more definite evidence is needed to justify this relatively expensive treatment.Cytotherapy 06/2013; 15(10). DOI:10.1016/j.jcyt.2013.03.011 · 3.10 Impact Factor
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ABSTRACT: Natural killer (NK) cells constitute a minor subset of normal lymphocytes that initiate innate immune responses toward tumor and virus-infected cells. They can mediate spontaneous cytotoxicity toward these abnormal cells and rapidly secrete numerous cytokines and chemokines to promote subsequent adaptive immune responses. Significant progress has been made in the past 2 decades to improve our understanding of NK cell biology. Here we review recent discoveries, including a better comprehension of the "education" of NK cells to achieve functional competence during their maturation and the discovery of "memory" responses by NK cells, suggesting that they might also contribute to adaptive immunity. The improved understanding of NK cell biology has forged greater awareness that these cells play integral early roles in immune responses. In addition, several promising clinical therapies have been used to exploit NK cell functions in treating patients with cancer. As our molecular understanding improves, these and future immunotherapies should continue to provide promising strategies to exploit the unique functions of NK cells to treat cancer, infections, and other pathologic conditions.The Journal of allergy and clinical immunology 07/2013; 132(3). DOI:10.1016/j.jaci.2013.07.006 · 11.25 Impact Factor