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Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E - Front Immunol (2015)

Bottom Line: However, NK cells represent only a minor fraction of the human lymphocyte population.Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients.Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Cell Therapies Institute, Nova Southeastern University , Fort Lauderdale, FL , USA ; Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine (HERM), Karolinska University Hospital Huddinge, NOVUM , Stockholm , Sweden.

ABSTRACT
Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.

No MeSH data available.


Related in: MedlinePlus

NK cell therapy approaches.
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Figure 3: NK cell therapy approaches.

Mentions: In the last decade, several NK cell based anti-cancer products have been taken to clinical trial stage with promising clinical outcomes. However, in order to manufacture more efficient NK cell therapy products, it is essential to develop novel potential strategies such as genetic modification of NK cells (Figure 3). Although NK cells are inherently resistant to retroviral infections (96, 175–177), our group has significantly enhanced retroviral and lentiviral gene delivery to NK cells through enhanced proliferation and targeting intracellular viral defense mechanism by small molecule inhibitors (96). Therefore, it is easier to design genetically modified NK cells expressing cytokine transgenes, silenced inhibitory receptors, overexpressing activating receptors, or retargeting NK cells by expression of CARs on the cell surface. By genetically modifying NK cells to produce cytokines such as IL-2 or IL-15, their survival capacity and proliferation increase and their activation and anti-tumor activity in vivo are enhanced (83, 87, 88, 178, 179). To enhance the specificity for the target cells, NK cells can be modified to recognize antigens specifically expressed on the tumor cells.


Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E - Front Immunol (2015)

NK cell therapy approaches.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663254&req=5

Figure 3: NK cell therapy approaches.
Mentions: In the last decade, several NK cell based anti-cancer products have been taken to clinical trial stage with promising clinical outcomes. However, in order to manufacture more efficient NK cell therapy products, it is essential to develop novel potential strategies such as genetic modification of NK cells (Figure 3). Although NK cells are inherently resistant to retroviral infections (96, 175–177), our group has significantly enhanced retroviral and lentiviral gene delivery to NK cells through enhanced proliferation and targeting intracellular viral defense mechanism by small molecule inhibitors (96). Therefore, it is easier to design genetically modified NK cells expressing cytokine transgenes, silenced inhibitory receptors, overexpressing activating receptors, or retargeting NK cells by expression of CARs on the cell surface. By genetically modifying NK cells to produce cytokines such as IL-2 or IL-15, their survival capacity and proliferation increase and their activation and anti-tumor activity in vivo are enhanced (83, 87, 88, 178, 179). To enhance the specificity for the target cells, NK cells can be modified to recognize antigens specifically expressed on the tumor cells.

Bottom Line: However, NK cells represent only a minor fraction of the human lymphocyte population.Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients.Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Cell Therapies Institute, Nova Southeastern University , Fort Lauderdale, FL , USA ; Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine (HERM), Karolinska University Hospital Huddinge, NOVUM , Stockholm , Sweden.

ABSTRACT
Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.

No MeSH data available.


Related in: MedlinePlus