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Article ; Online: Leveraging natural killer cells for cancer immunotherapy.

Grossenbacher, Steven K / Aguilar, Ethan G / Murphy, William J

2017 Volume 9, Issue 6, Page(s) 487–497

Abstract: Natural killer (NK) cells are potent antitumor effector cells of the innate immune system. Based on their ability to eradicate tumors in vitro and in animal models, significant enthusiasm surrounds the prospect of leveraging human NK cells as vehicles ... ...

Abstract	Natural killer (NK) cells are potent antitumor effector cells of the innate immune system. Based on their ability to eradicate tumors in vitro and in animal models, significant enthusiasm surrounds the prospect of leveraging human NK cells as vehicles for cancer immunotherapy. While interest in manipulating the effector functions of NK cells has existed for over 30 years, there is renewed optimism for this approach today. Although T cells receive much of the clinical and preclinical attention when it comes to cancer immunotherapy, new strategies are utilizing adoptive NK-cell immunotherapy and monoclonal antibodies and engineered molecules which have been developed to specifically activate NK cells against tumors. Despite the numerous challenges associated with the preclinical and clinical development of NK cell-based therapies for cancer, NK cells possess many unique immunological properties and hold the potential to provide an effective means for cancer immunotherapy.
MeSH term(s)	Animals ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Immunotherapy, Adoptive/methods ; Killer Cells, Natural/immunology ; Killer Cells, Natural/transplantation ; Neoplasms/immunology ; Neoplasms/therapy ; Neoplastic Stem Cells/immunology
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents
Language	English
Publishing date	2017-04-20
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2495964-9
ISSN	1750-7448 ; 1750-743X
ISSN (online)	1750-7448
ISSN	1750-743X
DOI	10.2217/imt-2017-0013
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Article: Natural killer cell immunotherapy to target stem-like tumor cells.

Grossenbacher, Steven K / Canter, Robert J / Murphy, William J

Journal for immunotherapy of cancer

2016 Volume 4, Page(s) 19

Abstract: Advances in cancer immunotherapy are leading to its increasing and successful application for the treatment of solid-tissue cancers. Despite the recent advances there are still significant barriers, in particular, evidence for significant tumor ... ...

Abstract	Advances in cancer immunotherapy are leading to its increasing and successful application for the treatment of solid-tissue cancers. Despite the recent advances there are still significant barriers, in particular, evidence for significant tumor heterogeneity, both genetic and epigenetic that limit long-term efficacy. Subpopulations of "stem-like" tumor cells have been identified in nearly all human malignancies based on both morphologic and functional criteria. Also called cancer stem cells or CSCs, these quiescent cells display enhanced tumorigenic potential and are capable of repopulating tumors in the wake of traditional cytoreductive therapies. These CSCs may be best targeted via immunotherapy. Our lab has identified activated natural killer (NK) cell-based therapy as an effective method to target CSCs particularly after radiation therapy for solid tumors. Using a variety of in vitro and in vivo methods, including the utilization of primary tumor tissue and patient-derived xenografts, we observed that autologous and allogeneic NK cells possess the ability to preferentially kill stem-like cells or CSCs from freshly isolated patient samples representing a broad spectrum of tumor types, including pancreatic cancers, breast cancers, and sarcomas. The results indicated that CSCs express stress ligand molecules capable of being targeted by NKG2D on NK cells and that prior radiation therapy can both deplete the cycling non-CSCs bulk tumor population and upregulate these stress ligands on the CSC making this an effective combination approach.
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426
ISSN	2051-1426
DOI	10.1186/s40425-016-0124-2
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Article ; Online: Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy.

Luna, Jesus I / Grossenbacher, Steven K / Murphy, William J / Canter, Robert J

Expert opinion on biological therapy

2017 Volume 17, Issue 3, Page(s) 313–324

Abstract: Introduction: Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with 'stem-cell' like properties including quiescence and repopulation. Immunotherapy represents a ... ...

Abstract	Introduction: Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with 'stem-cell' like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs). Areas covered: Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. The authors review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non-CSCs and CSCs. Expert opinion: Unlike cytotoxic cancer treatments, NK cells can target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells.
MeSH term(s)	Animals ; Humans ; Immunotherapy/methods ; Killer Cells, Natural/immunology ; Neoplasms/immunology ; Neoplasms/therapy ; Neoplastic Stem Cells/immunology
Language	English
Publishing date	2017-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1080/14712598.2017.1271874
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Article: Immune targeting of cancer stem cells in gastrointestinal oncology.

Canter, Robert J / Grossenbacher, Steven K / Ames, Erik / Murphy, William J

Journal of gastrointestinal oncology

2016 Volume 7, Issue Suppl 1, Page(s) S1–S10

Abstract: The cancer stem cell (CSC) hypothesis postulates that a sub-population of quiescent cells exist within tumors which are resistant to conventional cytotoxic/anti-proliferative therapies. It is these CSCs which then seed tumor relapse, even in cases of ... ...

Abstract	The cancer stem cell (CSC) hypothesis postulates that a sub-population of quiescent cells exist within tumors which are resistant to conventional cytotoxic/anti-proliferative therapies. It is these CSCs which then seed tumor relapse, even in cases of apparent complete response to systemic therapy. Therefore, therapies, such as immunotherapy, which add a specific anti-CSC strategy to standard cytoreductive treatments may provide a promising new direction for future cancer therapies. CSCs are an attractive target for immune therapies since, unlike chemotherapy or radiotherapy, immune effector cells do not specifically require target cells to be proliferating in order to effectively kill them. Although recent advances have been made in the development of novel systemic and targeted therapies for advanced gastro-intestinal (GI) malignancies, there remains an unmet need for durable new therapies for these refractory malignancies. Novel immunotherapeutic strategies targeting CSCs are in pre-clinical and clinical development across the spectrum of the immune system, including strategies utilizing adaptive immune cell-based effectors, innate immune effectors, as well as vaccine approaches. Lastly, since important CSC functions are affected by the tumor microenvironment, targeting of both cellular (myeloid derived suppressor cells and tumor-associated macrophages) and sub-cellular (cytokines, chemokines, and PD1/PDL1) components of the tumor microenvironment is under investigation in the immune targeting of CSCs. These efforts are adding to the significant optimism about the potential utility of immunotherapy to overcome cancer resistance mechanisms and cure greater numbers of patients with advanced malignancy.
Language	English
Publishing date	2016-03-31
Publishing country	China
Document type	Journal Article ; Review
ZDB-ID	2594644-4
ISSN	2219-679X ; 2078-6891
ISSN (online)	2219-679X
ISSN	2078-6891
DOI	10.3978/j.issn.2078-6891.2015.066
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Article ; Online: Models to Study NK Cell Biology and Possible Clinical Application.

Zamora, Anthony E / Grossenbacher, Steven K / Aguilar, Ethan G / Murphy, William J

Current protocols in immunology

2015 Volume 110, Page(s) 14.37.1–14.37.14

Abstract: Natural killer (NK) cells are large granular lymphocytes of the innate immune system, responsible for direct targeting and killing of both virally infected and transformed cells. NK cells rapidly recognize and respond to abnormal cells in the absence of ... ...

Abstract	Natural killer (NK) cells are large granular lymphocytes of the innate immune system, responsible for direct targeting and killing of both virally infected and transformed cells. NK cells rapidly recognize and respond to abnormal cells in the absence of prior sensitization due to their wide array of germline-encoded inhibitory and activating receptors, which differs from the receptor diversity found in B and T lymphocytes that is due to the use of recombination-activation gene (RAG) enzymes. Although NK cells have traditionally been described as natural killers that provide a first line of defense prior to the induction of adaptive immunity, a more complex view of NK cells is beginning to emerge, indicating they may also function in various immunoregulatory roles and have the capacity to shape adaptive immune responses. With the growing appreciation for the diverse functions of NK cells, and recent technological advancements that allow for a more in-depth understanding of NK cell biology, we can now begin to explore new ways to manipulate NK cells to increase their clinical utility. In this overview unit, we introduce the reader to various aspects of NK cell biology by reviewing topics ranging from NK cell diversity and function, mouse models, and the roles of NK cells in health and disease, to potential clinical applications. © 2015 by John Wiley & Sons, Inc.
MeSH term(s)	Animals ; Cell Differentiation ; Disease Models, Animal ; Disease Susceptibility ; Humans ; Immunity ; Immunotherapy/methods ; Killer Cells, Natural/cytology ; Killer Cells, Natural/physiology ; Lymphocyte Subsets/cytology ; Lymphocyte Subsets/physiology ; Mice ; Mice, Knockout ; Mice, Transgenic ; Phenotype ; Receptors, Natural Killer Cell/metabolism
Chemical Substances	Receptors, Natural Killer Cell
Language	English
Publishing date	2015-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1934-368X
ISSN (online)	1934-368X
DOI	10.1002/0471142735.im1437s110
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Article ; Online: PARP-1 deletion promotes subventricular zone neural stem cells toward a glial fate.

Plane, Jennifer M / Grossenbacher, Steven K / Deng, Wenbin

Journal of neuroscience research

2012 Volume 90, Issue 8, Page(s) 1489–1506

Abstract: Identification of critical factors involved in oligodendroglial fate specification from endogenous neural stem cells is relevant to the development of therapeutic interventions that aim to promote remyelination. Here we report a novel role of the DNA ... ...

Abstract	Identification of critical factors involved in oligodendroglial fate specification from endogenous neural stem cells is relevant to the development of therapeutic interventions that aim to promote remyelination. Here we report a novel role of the DNA repair protein poly-ADP-ribose polymerase-1 (PARP-1) in regulating the neural stem cell profile in the postnatal mouse forebrain subventricular zone (SVZ). We observed increased expression of Sox2 and Sox10 in the SVZ of postnatal day 11 (P11) PARP-1 knockout mice. This increase corresponded to increased Olig2 expression in Sox2-positive cells of the PARP-1 knockout mouse SVZ and decreased Map2abc expression compared with Sox2/Olig2 and Sox2/Map2abc expression in wild-type mice. We noted enhanced expression of proliferating oligodendrocyte progenitor cells (OPCs) at the expense of proliferating neuroblasts in the SVZ of PARP-1 knockout mice, by using Olig1/Ki67/DCX, NG2/Ki67/DCX, and PDGFR/BrdU/TuJ1 immunofluorescence labeling. In addition, the percentage of BrdU/Olig2 double-labeled cells increased in the SVZ and corpus callosum of PARP-1 knockout mice compared with wild-type mice. We also observed a decrease in DCX-positive cells without a decrease in the overall SVZ area in PARP-1 knockout mice, further indicating a switch from neuroblast to OPC fate. PARP-1 knockout mice displayed thinning of MBP expression in the corpus callosum and external capsule, suggesting that the enhanced OPC proliferation in the SVZ might compensate for deficiency in myelination. Together, our results show that PARP-1 deletion promotes SVZ neural stem cells toward a glial fate and suggest that future studies target PARP-1 as a potential therapeutic strategy for demyelinating diseases.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Cell Lineage ; Fluorescent Antibody Technique ; Mice ; Mice, Knockout ; Neural Stem Cells/cytology ; Neural Stem Cells/enzymology ; Neurogenesis/physiology ; Neuroglia/cytology ; Neuroglia/enzymology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/deficiency ; Poly(ADP-ribose) Polymerases/metabolism ; Prosencephalon/cytology ; Prosencephalon/enzymology ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Parp1 protein, mouse (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2012-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.23040
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Zs.A 1232: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
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Article: Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells.

Luna, Jesus I / Grossenbacher, Steven K / Sturgill, Ian R / Ames, Erik / Judge, Sean J / Bouzid, Lyes A / Darrow, Morgan A / Murphy, William J / Canter, Robert J

Cancers

2019 Volume 11, Issue 1

Abstract: Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as ... ...

Abstract	Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.
Language	English
Publishing date	2019-01-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11010085
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Article: Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells.

Ames, Erik / Canter, Robert J / Grossenbacher, Steven K / Mac, Stephanie / Smith, Rachel C / Monjazeb, Arta M / Chen, Mingyi / Murphy, William J

Oncoimmunology

2015 Volume 4, Issue 9, Page(s) e1036212

Abstract: Natural killer (NK) cells are innate lymphocytes postulated to mediate resistance against primary haematopoietic but not solid tumor malignancies. Cancer stem cells (CSCs) are a small subset of malignant cells with stem-like properties which are ... ...

Abstract	Natural killer (NK) cells are innate lymphocytes postulated to mediate resistance against primary haematopoietic but not solid tumor malignancies. Cancer stem cells (CSCs) are a small subset of malignant cells with stem-like properties which are resistant to chemo- and radiotherapies and are able to repopulate a tumor after cytoreductive treatments. We observed increased frequencies of stem-like tumor cells after irradiation, with increased expression of stress ligands on surviving stem-like cells.
Language	English
Publishing date	2015-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2015.1036212
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Article: Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer.

Mall, Christine / Sckisel, Gail D / Proia, David A / Mirsoian, Annie / Grossenbacher, Steven K / Pai, Chien-Chun Steven / Chen, Mingyi / Monjazeb, Arta M / Kelly, Karen / Blazar, Bruce R / Murphy, William J

Oncoimmunology

2015 Volume 5, Issue 2, Page(s) e1075114

Abstract: Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, ... ...

Abstract	Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30-60 min after 4-5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1
Language	English
Publishing date	2015-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2015.1075114
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Article: Immunoediting and antigen loss: overcoming the achilles heel of immunotherapy with antigen non-specific therapies.

Monjazeb, Arta Monir / Zamora, Anthony E / Grossenbacher, Steven K / Mirsoian, Annie / Sckisel, Gail D / Murphy, William J

Frontiers in oncology

2013 Volume 3, Page(s) 197

Abstract: Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. Clinical translation has failed to ... ...

Abstract	Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. Clinical translation has failed to recapitulate the promising results of pre-clinical studies although there have been some successes. In this review we explore some of the short-comings of cancer immunotherapy that have limited successful clinical translation. We will give special consideration to what we consider the most formidable hurdle to successful cancer immunotherapy: tumor-induced immune suppression and immune escape. We will discuss the need for antigen-specific immune responses for successful immunotherapy but also consider the need for antigen specificity as an Achilles heel of immunotherapy given tumor heterogeneity, immune editing, and antigen loss. Finally, we will discuss how combinatorial strategies may overcome some of the pitfalls of antigen specificity and highlight recent studies from our lab which suggest that the induction of antigen non-specific immune responses may also produce robust anti-tumor effects and bypass the need for antigen specificity.
Language	English
Publishing date	2013-07-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2013.00197
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