Characterization of Cord Blood Natural Killer and Lymphokine Activated Killer Lymphocytes Following Ex Vivo Cellular Engineering

Ayello, Janet; Ven, Carmella van de; Fortino, Weiwei; Wade-Harris, C.; Satwani, Prakash; Baxi, Laxmi; Simpson, Lynn L.; Sanger, Warren G.; Pickering, Diana; Kurtzberg, Joanne; Cairo, Mitchell S.

doi:10.1016/j.bbmt.2006.01.009

Cited by 30 publications

(20 citation statements)

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“…Studies have shown that CB contains a higher percentage of NK cells than adult peripheral blood (PB) [7, 8]. Although NK cells in CB are reported to have lower cytotoxic function than PB, cytotoxicity can be significantly increased by activation with a cytokine cocktail, often containing IL-2 or IL-15 [7, 9–14]. Alternatively, NK cell cytotoxic function has also been augmented by the use of chimeric antigen receptor or artificial antigen presenting feeder cells [15–18].…”

Section: Introductionmentioning

confidence: 99%

“…While current studies have demonstrated that CB NK cell have heterogeneous KIR profiles, most studies have focused on freshly isolated NK cells [20]. Few studies have examined KIR profiles in NK cells before and after culture [12–14]. Additional studies in the field of NK cells, their receptors and their ligands may aid in determining the role of KIR-ligand mismatching after CBT.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Cytotoxic Function of Natural Killer and CD3+CD56+ Cells in Cord Blood after Culture

Tomchuck

Leung

Dallas

2015

Biology of Blood and Marrow Transplantation

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Rate of immune reconstitution (IR) directly correlates with the number of hematopoietic stem cells (HSC) infused and is particularly delayed in patients undergoing cord blood (CB) transplantation (CBT). Methods to increase the number of CB natural killer (NK) cells have the potential to improve IR after CBT. NK cells are the first lymphocyte population to recover after HSC transplant and are central to preventing early relapse and infection. CB NK cells are low in number and are known to be incomplete in maturation and require activation for effective function. Here, we report a clinically relevant ex vivo expansion method that increases the number of activated CB NK cells. We report a multi-log increase in NK cell number when CB mononuclear cells (CBMC) are co-cultured with interleukin (IL)-2 and IL-15 resulted. Furthermore, NK cells expressing activating receptors and adhesion molecules responsible for cytotoxicity increased throughout culture while inhibitory receptor expression remained low. Additionally, cytotoxic function against various malignancies was significantly enhanced in cultured NK cells but not CD3+CD56+ cells. These data suggest that ex vivo expansion and activation of CB NK cells is a clinically feasible and relevant approach to prevent early infection and relapse after CBT.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced Cytotoxic Function of Natural Killer and CD3+CD56+ Cells in Cord Blood after Culture

Tomchuck

Leung

Dallas

2015

Biology of Blood and Marrow Transplantation

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“…Activation of autologous T cells can mediate NK cell expansion, presumably also through release of local cytokine 3 . Support with mesenchymal stroma or artificial antigen presenting cells (aAPCs) can support the expansion of NK cells from both peripheral blood and cord blood 4 . Combined NKp46 and CD2 activation by antibodycoated beads is currently marketed for NK cell expansion (Miltenyi Biotec, Auburn CA), resulting in approximately 100-fold expansion in 21 days.…”

mentioning

confidence: 99%

Expansion, Purification, and Functional Assessment of Human Peripheral Blood NK Cells

Somanchi

Senyukov

Denman

et al. 2011

JoVE

121

147

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Natural killer (NK) cells play an important role in immune surveillance against a variety of infectious microorganisms and tumors. Limited availability of NK cells and ability to expand in vitro has restricted development of NK cell immunotherapy. Here we describe a method to efficiently expand vast quantities of functional NK cells ex vivo using K562 cells expressing membrane-bound IL21, as an artificial antigen-presenting cell (aAPC). NK cell adoptive therapies to date have utilized a cell product obtained by steady-state leukapheresis of the donor followed by depletion of T cells or positive selection of NK cells. The product is usually activated in IL-2 overnight and then administered the following day. Because of the low frequency of NK cells in peripheral blood, relatively small numbers of NK cells have been delivered in clinical trials. The inability to propagate NK cells in vitro has been the limiting factor for generating sufficient cell numbers for optimal clinical outcome. Some expansion of NK cells (5-10 fold over 1-2 weeks) has be achieved through high-dose IL-2 alone. Activation of autologous T cells can mediate NK cell expansion, presumably also through release of local cytokine. Support with mesenchymal stroma or artificial antigen presenting cells (aAPCs) can support the expansion of NK cells from both peripheral blood and cord blood. Combined NKp46 and CD2 activation by antibody-coated beads is currently marketed for NK cell expansion (Miltenyi Biotec, Auburn CA), resulting in approximately 100-fold expansion in 21 days. Clinical trials using aAPC-expanded or -activated NK cells are underway, one using leukemic cell line CTV-1 to prime and activate NK cells without significant expansion. A second trial utilizes EBV-LCL for NK cell expansion, achieving a mean 490-fold expansion in 21 days. The third utilizes a K562-based aAPC transduced with 4-1BBL (CD137L) and membrane-bound IL-15 (mIL-15), which achieved a mean NK expansion 277-fold in 21 days. Although, the NK cells expanded using K562-41BBL-mIL15 aAPC are highly cytotoxic in vitro and in vivo compared to unexpanded NK cells, and participate in ADCC, their proliferation is limited by senescence attributed to telomere shortening. More recently a 350-fold expansion of NK cells was reported using K562 expressing MICA, 4-1BBL and IL15. Our method of NK cell expansion described herein produces rapid proliferation of NK cells without senescence achieving a median 21,000-fold expansion in 21 days.

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“…To overcome these limitations, many groups have developed techniques for ex vivo expansion of NK cells adapted to UCB as the starting source to enable adoptive immunotherapy. [39][40][41][42][43][44][45][46][47][48] In addition, ex vivo IL-2-expanded NK cells from CB were shown to be active against AML blasts and showed anti-leukemia activity in vivo when infused into mice bearing human AML. 49 NK cell-based cancer immunotherapy is an expanding scientific area of investigation.…”

Section: Co-administration Of Cb and Hpdscsmentioning

confidence: 99%

Cellular engineering and therapy in combination with cord blood allografting in pediatric recipients

Cairo

Tarek

Lee

et al. 2015

Bone Marrow Transplant

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Cord blood (CB) transplantation is an alternate source of human hematopoietic progenitor cells for allogeneic stem cell transplantation in children and adolescents with both malignant and nonmalignant diseases. Current limitations included delay in hematopoietic reconstitution, increased incidence of primary graft failure and slow cellular immunoreconstitution. These limitations lead to a significant increase in primary graft failure, infectious complications and increased transplant-related mortality. There is a number of experimental approaches currently under investigation including cellular engineering to circumvent these limitations. In this review, we summarize the recent findings of utilizing ex vivo CB expansion with Notch1 ligand Delta 1, mesenchymal progenitor cells, the use of human placenta-derived stem cells and CB-derived natural killer cells. Early and preliminary results suggest some of these experimental cellular strategies may in part ameliorate the incidence of primary graft failure, delays in hematopoietic reconstitution and/or slowness in cellular immune reconstitution following unrelated CB transplantation.

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Characterization of Cord Blood Natural Killer and Lymphokine Activated Killer Lymphocytes Following Ex Vivo Cellular Engineering

Cited by 30 publications

References 50 publications

Enhanced Cytotoxic Function of Natural Killer and CD3+CD56+ Cells in Cord Blood after Culture

Enhanced Cytotoxic Function of Natural Killer and CD3+CD56+ Cells in Cord Blood after Culture

Expansion, Purification, and Functional Assessment of Human Peripheral Blood NK Cells

Cellular engineering and therapy in combination with cord blood allografting in pediatric recipients

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