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Development of Cytotoxic Natural Killer Cells for Ovarian Cancer Treatment

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Date Issued:
2015
Abstract/Description:
Ovarian cancer is a leading cause of gynecological malignancy. Cytoreductive surgery and frontline platinum/taxane-based chemotherapy provides good initial efficacy in the treatment, but poor long-term patient survival. This is mainly caused by tumor relapse due to intraperitoneal spreading and ineffective alternate therapies to treat these resistant tumors. The challenge in the field is to develop strategies that would prove effective in these patients and extend overall survival.Over the years, various treatments have been developed for the treatment of cancer amongst which, adoptive cell immunotherapy has shown promising results. But despite the efficacy seen in the clinic, there are concerns with the complexity of treatment and associated side effects. Therefore, there is still a need for better understanding of how different components of the immune system react to the presence of tumor. In this study, healthy human peripheral blood mononuclear cells (PBMCs) were used to examine the immune response in a mouse model with residual human ovarian tumor, where natural killer (NK) cells were found to be the effector cells that elicited an anti-tumor response. Presence of tumor was found to stimulate NK cell expansion and cytotoxicity in mice treated intraperitoneally (IP) with PBMCs+Interleukin-2 (IL- 2). Intravenous (IV) adoptive transfer of isolated NK cells has been attempted in ovarian cancer patients before, but showed lack of persistence in patients resulting in lack of anti-tumor efficacy. Experiments in this study highlight the significance of NK cell-cytotoxic response to tumor, which may be attributed to interacting immune cell types in the PBMC population (when treated IP), as opposed to clinically used isolated NK cells showing lack of anti-tumor efficacy in ovarian cancer patients (when treated IV).iiiNK cell immunotherapy is mainly limited by insufficient numbers generated for adoptive transfer, limited in vivo life span after adoptive transfer, lack of cytotoxicity and some logistical concerns that impede its widespread implementation. Therefore there is a need to develop methods of NK cell expansion that provide stimulation similar to other immune cell types in the PBMC population. The second part of this study utilizes a method of in vivo NK cell expansion using a particle-based approach in which plasma membranes of K562-MB21-41BBL cells (K562 cells expressing membrane-bound IL-21 and 41BB ligand) are used for specific NK cell expansion from PBMCs. NK cells expanded with this method were cytotoxic, showed in vivo persistence and biodistribution in different organs.Collectively, these studies show that NK cells are a major innate immune component that can recognize and kill the tumor. Their cytotoxic ability, using particle-based stimulation, can be enhanced for a second-line treatment of relapsed tumors such as in ovarian cancer as well as other cancer types.
Title: Development of Cytotoxic Natural Killer Cells for Ovarian Cancer Treatment.
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Name(s): Pandey, Veethika, Author
Altomare, Deborah, Committee Chair
Zhao, Jihe, Committee Member
Khaled, Annette, Committee Member
Estevez, Alvaro, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2015
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Ovarian cancer is a leading cause of gynecological malignancy. Cytoreductive surgery and frontline platinum/taxane-based chemotherapy provides good initial efficacy in the treatment, but poor long-term patient survival. This is mainly caused by tumor relapse due to intraperitoneal spreading and ineffective alternate therapies to treat these resistant tumors. The challenge in the field is to develop strategies that would prove effective in these patients and extend overall survival.Over the years, various treatments have been developed for the treatment of cancer amongst which, adoptive cell immunotherapy has shown promising results. But despite the efficacy seen in the clinic, there are concerns with the complexity of treatment and associated side effects. Therefore, there is still a need for better understanding of how different components of the immune system react to the presence of tumor. In this study, healthy human peripheral blood mononuclear cells (PBMCs) were used to examine the immune response in a mouse model with residual human ovarian tumor, where natural killer (NK) cells were found to be the effector cells that elicited an anti-tumor response. Presence of tumor was found to stimulate NK cell expansion and cytotoxicity in mice treated intraperitoneally (IP) with PBMCs+Interleukin-2 (IL- 2). Intravenous (IV) adoptive transfer of isolated NK cells has been attempted in ovarian cancer patients before, but showed lack of persistence in patients resulting in lack of anti-tumor efficacy. Experiments in this study highlight the significance of NK cell-cytotoxic response to tumor, which may be attributed to interacting immune cell types in the PBMC population (when treated IP), as opposed to clinically used isolated NK cells showing lack of anti-tumor efficacy in ovarian cancer patients (when treated IV).iiiNK cell immunotherapy is mainly limited by insufficient numbers generated for adoptive transfer, limited in vivo life span after adoptive transfer, lack of cytotoxicity and some logistical concerns that impede its widespread implementation. Therefore there is a need to develop methods of NK cell expansion that provide stimulation similar to other immune cell types in the PBMC population. The second part of this study utilizes a method of in vivo NK cell expansion using a particle-based approach in which plasma membranes of K562-MB21-41BBL cells (K562 cells expressing membrane-bound IL-21 and 41BB ligand) are used for specific NK cell expansion from PBMCs. NK cells expanded with this method were cytotoxic, showed in vivo persistence and biodistribution in different organs.Collectively, these studies show that NK cells are a major innate immune component that can recognize and kill the tumor. Their cytotoxic ability, using particle-based stimulation, can be enhanced for a second-line treatment of relapsed tumors such as in ovarian cancer as well as other cancer types.
Identifier: CFE0006369 (IID), ucf:51531 (fedora)
Note(s): 2015-12-01
Ph.D.
Medicine, Burnett School of Biomedical Sciences
Doctoral
This record was generated from author submitted information.
Subject(s): preclinical -- adoptive cell transfer -- Natural Killer cells -- allogeneic peripheral blood mononuclear cells -- ovarian cancer
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0006369
Restrictions on Access: public 2016-06-15
Host Institution: UCF

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