A Two-Phase Expansion Protocol Combining Interleukin (IL)-15 and IL-21 Improves Natural Killer Cell Proliferation and Cytotoxicity against Rhabdomyosarcoma

  title={A Two-Phase Expansion Protocol Combining Interleukin (IL)-15 and IL-21 Improves Natural Killer Cell Proliferation and Cytotoxicity against Rhabdomyosarcoma},
  author={Juliane Wagner and Viktoria Pfannenstiel and Anja Waldmann and Judith Bergs and Boris Brill and Sabine Huenecke and Thomas Klingebiel and Franz R{\"o}del and Christian J. Buchholz and Winfried S. Wels and Peter Bader and Evelyn Ullrich},
  journal={Frontiers in Immunology},
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children. Despite intensive research in recent decades the prognosis for patients with metastatic or relapsed diseases has hardly improved. New therapeutic concepts in anti-tumor therapy aim to modulate the patient’s immune system to increase its aggressiveness or targeted effects toward tumor cells. Besides surgery, radiotherapy and chemotherapy, immune activation by direct application of cytokines, antibodies or adoptive cell… 

The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation

It is revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation.

NK cells and ILCs in tumor immunotherapy.

NK Cell-Based Immunotherapy for Hematological Malignancies

Preliminary results suggest that engineering of mature NK cells through chimeric antigen receptor (CAR) constructs deserve further investigation, with the goal of obtaining an “off-the-shelf” NK cell bank that may serve many different recipients for granting an efficient antileukemia activity.

Enhancing Natural Killer Cell Targeting of Pediatric Sarcoma

The evidence for the current and future strategies to enhance the NK cell-versus-pediatric sarcoma effect is discussed, with a clinical focus, including enhancing antibody-dependent NK cell cytotoxicity, counteracting theNK cell mechanisms of self-tolerance, and developing adoptive NK cell therapy including chimeric antigen receptor-expressing NK cells.

Prospects for NK Cell Therapy of Sarcoma

The current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis is reviewed, as well as the molecular mechanisms behind Sarcoma-mediated NK cell suppression.

Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

The challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations are introduced, followed by an outline of the recent preclinical advances and the latest clinical outcomes of NK-based immunotherapies, as well as promising strategies to optimize current NK-targeted immunotherAPies for solid tumors.

Engineered NK Cells Against Cancer and Their Potential Applications Beyond

Recent literature suggests that Natural Killer cells, may provide a safer alternative and an ‘off-the-shelf’ treatment option thanks to their potent antitumor properties and relatively short lifespan.

Inducible MyD88/CD40 synergizes with IL-15 to enhance antitumor efficacy of CAR-NK cells.

CAR-NK cells utilizing dual molecular switches provide an innovative and effective approach to cancer immunotherapy with controlled specificity, efficacy, and safety.

Advances in NK cell production

Recent advances in expansion strategies with or without genetic manipulation of NK cells derived from various cellular sources are summarized and possible future NK cell-based immunotherapy products are discussed.



A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer

In conclusion, repetitive infusions of allogeneic, in vitro activated and expanded with IL-15/HC NK cells, in combination with chemotherapy are safe and potentially clinically effective.

Modifying interleukin-2 concentrations during culture improves function of T cells for adoptive immunotherapy.

Fine tuning of the IL-2 concentration during ex vivo expansion of T cells can yield high numbers of T cell with optimal features for clinical use.

Role of NKG2D, DNAM-1 and natural cytotoxicity receptors in cytotoxicity toward rhabdomyosarcoma cell lines mediated by resting and IL-15-activated human natural killer cells

The potential of resting and cytokine-activated natural killer (NK) cells to lyse RMS cell lines, as well as the pathways involved, are investigated, to explore the eventual clinical application of (activated) NK cell immunotherapy.

Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.

It is suggested that haploidentical NK cells can persist and expand in vivo and may have a role in the treatment of selected malignancies used alone or as an adjunct to HCT.

Multiple effects of IL-21 on human NK cells in ex vivo expansion.

Allogeneic natural killer cells for refractory lymphoma

The findings suggest safety and feasibility of allogeneic NK cell therapy in patients with lymphoma; however host Treg and inadequate immunodepletion may contribute to a hostile milieu for NK cell survival and expansion.

Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma

A protocol for ex vivo NK cell expansion that results in outstanding cell yields is developed and possesses potent antitumor activity in vitro and in vivo and could be utilized at high numbers for adoptive immunotherapy in the clinic.

Shaping of Natural Killer Cell Antitumor Activity by Ex Vivo Cultivation

The current knowledge on NK cell modulation by different ex vivo cultivation strategies focused on increasing NK cytotoxicity for clinical application in malignant diseases is summarized.

Large scale ex vivo expansion and activation of human natural killer cells for autologous therapy.

It is demonstrated that ANK generated in high dose IL-2 maintain NK and LAK activity for up to 6 days when cultured in as little as 1 U/ml rIL-2, which may allow infusion of ANK with a ril-2 dose achievable in vivo that does not produce significant systemic toxicity.