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Article ; Online: Suppressive effects of obesity on NK cells: is it time to incorporate obesity as a clinical variable for NK cell-based cancer immunotherapy regimens?

Canter, Robert J / Judge, Sean J / Collins, Craig P / Yoon, Daniel Jaeho / Murphy, William J

2024 Volume 12, Issue 3

MeSH term(s)	Humans ; Killer Cells, Natural ; Immunotherapy ; Neoplasms/therapy ; Obesity/therapy
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-008443
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Article ; Online: ASO Author Reflections: The Central Role of Chemotherapy in Patients with Advanced Cancer Recently Diagnosed with Malignant Bowel Obstruction.

Bateni, Sarah B / Canter, Robert J

Annals of surgical oncology

2021 Volume 28, Issue 12, Page(s) 7564–7565

MeSH term(s)	Humans ; Intestinal Obstruction ; Neoadjuvant Therapy ; Neoplasms
Language	English
Publishing date	2021-03-22
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1200469-8
ISSN	1534-4681 ; 1068-9265
ISSN (online)	1534-4681
ISSN	1068-9265
DOI	10.1245/s10434-021-09850-x
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Article ; Online: Multifaceted effects of obesity on cancer immunotherapies: Bridging preclinical models and clinical data.

Vick, Logan V / Canter, Robert J / Monjazeb, Arta M / Murphy, William J

Seminars in cancer biology

2023 Volume 95, Page(s) 88–102

Abstract: Obesity, defined by excessive body fat, is a highly complex condition affecting numerous physiological processes, such as metabolism, proliferation, and cellular homeostasis. These multifaceted effects impact cells and tissues throughout the host, ... ...

Abstract	Obesity, defined by excessive body fat, is a highly complex condition affecting numerous physiological processes, such as metabolism, proliferation, and cellular homeostasis. These multifaceted effects impact cells and tissues throughout the host, including immune cells as well as cancer biology. Because of the multifaceted nature of obesity, common parameters used to define it (such as body mass index in humans) can be problematic, and more nuanced methods are needed to characterize the pleiotropic metabolic effects of obesity. Obesity is well-accepted as an overall negative prognostic factor for cancer incidence, progression, and outcome. This is in part due to the meta-inflammatory and immunosuppressive effects of obesity. Immunotherapy is increasingly used in cancer therapy, and there are many different types of immunotherapy approaches. The effects of obesity on immunotherapy have only recently been studied with the demonstration of an "obesity paradox", in which some immune therapies have been demonstrated to result in greater efficacy in obese subjects despite the direct adverse effects of obesity and excess body fat acting on the cancer itself. The multifactorial characteristics that influence the effects of obesity (age, sex, lean muscle mass, underlying metabolic conditions and drugs) further confound interpretation of clinical data and necessitate the use of more relevant preclinical models mirroring these variables in the human scenario. Such models will allow for more nuanced mechanistic assessment of how obesity can impact, both positively and negatively, cancer biology, host metabolism, immune regulation, and how these intersecting processes impact the delivery and outcome of cancer immunotherapy.
MeSH term(s)	Humans ; Obesity/complications ; Obesity/metabolism ; Body Mass Index ; Neoplasms/etiology ; Neoplasms/therapy ; Immunotherapy/adverse effects
Language	English
Publishing date	2023-07-26
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2023.07.004
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Article ; Online: Regionalization of pancreatic surgery in California: Benefits for preventing postoperative deaths and reducing healthcare costs.

Perry, Lauren M / Canter, Robert J / Gaskill, Cameron E / Bold, Richard J

Surgery open science

2023 Volume 16, Page(s) 198–204

Abstract: Introduction: Pancreatic cancer (PC) surgery has been associated with improved outcomes and value when performed at high-volume centers (HVC; ≥20 surgeries annually) compared to low-volume centers (LVC). Some have used these differences to suggest that ... ...

Abstract	Introduction: Pancreatic cancer (PC) surgery has been associated with improved outcomes and value when performed at high-volume centers (HVC; ≥20 surgeries annually) compared to low-volume centers (LVC). Some have used these differences to suggest that regionalization of PC surgery would optimize patient outcomes and expenditures. Methods: A Markov model was created to evaluate 30-day mortality, 30-day complications, and 30-day costs. The differences in these outcome measures between the current and future states were measured to assess the population-level benefits of regionalization. A sensitivity analysis was performed to evaluate the impact of variations of input variables in the model. Results: Among 5958 new cases of pancreatic cancer in California in 2021, a total of 2443 cases (41 %) would be resectable; among patients with resectable PC, a total of 977 (40 %) patients would undergo surgery. In aggregate, HVC and LVC 30-day postoperative complications occurred in 364 patients, 30-day mortality in 35 patients, and healthcare costs expended managing complications were $6,120,660. In the predictive model of complete regionalization to only HVC in California, an estimated 29 fewer complications, 17 fewer deaths, and a cost savings of $487,635 per year would occur. Conclusions and relevance: Pancreatic cancer (PC) surgery has been associated with improved outcomes and value when performed at high-volume centers (HVC; ≥20 surgeries annually) compared to low-volume centers (LVC). Complete regionalization of pancreatic cancer surgery predicted benefits in mortality, complications and cost, though implementing this strategy at a population-level may require investment of resources and redesigning care delivery models.
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article
ISSN	2589-8450
ISSN (online)	2589-8450
DOI	10.1016/j.sopen.2023.11.004
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Article: Improved characterization and translation of NK cells for canine immunotherapy.

Razmara, Aryana M / Gingrich, Alicia A / Toedebusch, Christine M / Rebhun, Robert B / Murphy, William J / Kent, Michael S / Canter, Robert J

Frontiers in veterinary science

2024 Volume 11, Page(s) 1336158

Abstract: The field of cancer immunology has seen a meteoric rise in interest and application due to the discovery of immunotherapies that target immune cells, often leading to dramatic anti-tumor effects. However, successful cellular immunotherapy for solid ... ...

Abstract	The field of cancer immunology has seen a meteoric rise in interest and application due to the discovery of immunotherapies that target immune cells, often leading to dramatic anti-tumor effects. However, successful cellular immunotherapy for solid tumors remains a challenge, and the application of immunotherapy to dogs with naturally occurring cancers has emerged as a high yield large animal model to bridge the bench-to-bedside challenges of immunotherapies, including those based on natural killer (NK) cells. Here, we review recent developments in the characterization and understanding of canine NK cells, a critical springboard for future translational NK immunotherapy research. The characterization of canine NK cells is exceptionally pertinent given the ongoing challenges in defining them and contextualizing their similarities and differences compared to human and murine NK cells compounded by the limited availability of validated canine specific reagents. Additionally, we summarize the current landscape of the clinical and translational literature employing strategies to capitalize on endogenous and exogenous NK cell immunotherapy in canine cancer patients. The insights regarding efficacy and immune correlates from these trials provide a solid foundation to design and test novel combinational therapies to enhance NK cell activity with the added benefit of motivating comparative work to translate these findings to human cancers with extensive similarities to their canine counterparts. The compilation of knowledge from basic canine NK phenotype and function to applications in first-in-dog clinical trials will support the canine cancer model and enhance translational work to improve cancer outcomes for both dogs and humans.
Language	English
Publishing date	2024-02-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2834243-4
ISSN	2297-1769
ISSN	2297-1769
DOI	10.3389/fvets.2024.1336158
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Article ; Online: Chemotherapy: Does Neoadjuvant or Adjuvant Therapy Improve Outcomes?

Canter, Robert J

Surgical oncology clinics of North America

2016 Volume 25, Issue 4, Page(s) 861–872

Abstract: Since preoperative chemotherapy has been clearly shown to improve outcomes for patients with Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, practitioners have attempted to extend the use of adjuvant/neoadjuvant chemotherapy to other types of adult ... ...

Abstract	Since preoperative chemotherapy has been clearly shown to improve outcomes for patients with Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, practitioners have attempted to extend the use of adjuvant/neoadjuvant chemotherapy to other types of adult soft tissue sarcoma. Given the high risk of distant recurrence and disease-specific death for patients with soft tissue sarcoma tumors larger than 10 cm, these patients should be considered candidates for neoadjuvant chemotherapy as well as investigational therapies. Yet, potential toxicity from cytotoxic chemotherapy is substantial, and there remains little consensus and wide variation regarding the indications for use of chemotherapy in the adjuvant/neoadjuvant setting.
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1196919-2
ISSN	1558-5042 ; 1055-3207
ISSN (online)	1558-5042
ISSN	1055-3207
DOI	10.1016/j.soc.2016.05.013
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Article ; Online: Surgical approach for soft tissue sarcoma: standard of care and future approaches.

Canter, Robert J

Current opinion in oncology

2015 Volume 27, Issue 4, Page(s) 343–348

Abstract: Purpose of review: This review highlights the ongoing importance of surgical resection as the primary treatment modality for localized soft tissue sarcomas (STSs) in all locations and for the majority of histologic types. Accomplishing this goal in an ... ...

Abstract	Purpose of review: This review highlights the ongoing importance of surgical resection as the primary treatment modality for localized soft tissue sarcomas (STSs) in all locations and for the majority of histologic types. Accomplishing this goal in an oncologic fashion is of paramount importance for all patients eligible for treatment with curative intent and for selected patients with metastatic disease. Recent findings: Ongoing advances in combined modality therapy and improved knowledge regarding the natural history and disease biology of individual sarcoma subtypes have allowed for better surgical planning and tailoring of the extent of resection depending on individual clinical, radiographic, and pathologic factors. Summary: Successful therapy for localized STS remains contingent on surgical resection with tumor-free margins. It is hoped that ongoing advances in the molecular and genetic understanding of the pathogenesis and biology of STS will lead to sustained improvements in the care of these patients, and success will come from the ongoing development of targeted therapies and immunotherapies specific to histologic type.
MeSH term(s)	Humans ; Sarcoma/pathology ; Sarcoma/surgery ; Standard of Care
Language	English
Publishing date	2015-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1049384-0
ISSN	1531-703X ; 1040-8746
ISSN (online)	1531-703X
ISSN	1040-8746
DOI	10.1097/CCO.0000000000000202
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Article ; Online: Preclinical evaluation and first-in-dog clinical trials of PBMC-expanded natural killer cells for adoptive immunotherapy in dogs with cancer.

Razmara, Aryana M / Farley, Lauren E / Harris, Rayna M / Judge, Sean J / Lammers, Marshall / Iranpur, Khurshid R / Johnson, Eric G / Dunai, Cordelia / Murphy, William J / Brown, C Titus / Rebhun, Robert B / Kent, Michael S / Canter, Robert J

Journal for immunotherapy of cancer

2024 Volume 12, Issue 4

Abstract: Background: Natural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in ... ...

Abstract	Background: Natural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in the context of an intact immune system, representing a valid cancer immunotherapy model. Previously, CD5 depletion of peripheral blood mononuclear cells (PBMCs) was used in dogs to isolate a CD5 Methods: Starting populations of CD5-depleted cells and PBMCs from healthy beagle donors were co-cultured for 14 days, phenotype, cytotoxicity, and cytokine secretion were measured, and samples were sequenced using the 3'-Tag-RNA-Seq protocol. Co-cultured human PBMCs and NK-isolated cells were also sequenced for comparative analysis. In addition, two first-in-dog clinical trials were performed in dogs with melanoma and osteosarcoma using autologous and allogeneic NK cells, respectively, to establish safety and proof-of-concept of this manufacturing approach. Results: Calculated cell counts, viability, killing, and cytokine secretion were equivalent or higher in expanded NK cells from canine PBMCs versus CD5-depleted cells, and immune phenotyping confirmed a CD3-NKp46+ product from PBMC-expanded cells at day 14. Transcriptomic analysis of expanded cell populations confirmed upregulation of NK activation genes and related pathways, and human NK cells using well-characterized NK markers closely mirrored canine gene expression patterns. Autologous and allogeneic PBMC-derived NK cells were successfully expanded for use in first-in-dog clinical trials, resulting in no serious adverse events and preliminary efficacy data. RNA sequencing of PBMCs from dogs receiving allogeneic NK transfer showed patient-unique gene signatures with NK gene expression trends in response to treatment. Conclusions: Overall, the use of unmanipulated PBMCs appears safe and potentially effective for canine NK immunotherapy with equivalent to superior results to CD5 depletion in NK expansion, activation, and cytotoxicity. Our preclinical and clinical data support further evaluation of this technique as a novel platform for optimizing NK immunotherapy in dogs.
MeSH term(s)	Dogs ; Animals ; Humans ; Immunotherapy, Adoptive ; Leukocytes, Mononuclear ; Cytotoxicity, Immunologic ; Killer Cells, Natural ; Osteosarcoma/veterinary ; Bone Neoplasms/metabolism ; Cytokines/metabolism
Chemical Substances	Cytokines
Language	English
Publishing date	2024-04-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007963
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Article ; Online: Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence.

Judge, Sean J / Murphy, William J / Canter, Robert J

Frontiers in cellular and infection microbiology

2020 Volume 10, Page(s) 49

Abstract: There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules ... ...

Abstract	There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules associated with immune exhaustion (such as PD-1, but also TIGIT, and LAG-3) has led to a revolution in oncology with dramatic benefits in a growing list of solid and hematologic malignancies. Given this success in reinvigorating exhausted T cells and the related anti-tumor effects, there are increasing efforts to apply immune checkpoint blockade to other exhausted immune cells beyond T cells. One approach involves the reinvigoration of "exhausted" NK cells, a non-T, non-B lymphoid cell of the innate immune system. However, in contrast to the more well-defined and established molecular, genetic, and immunophenotypic characteristics of T cell exhaustion, a consensus on the defining functional and phenotypic features of NK "exhaustion" is less clear. As is well-known from T cell biology, separate and distinct molecular and cellular processes including senescence, anergy and exhaustion can lead to diminished immune effector function with different implications for immune regulation and recovery. For NK cells, it is unclear if exhaustion, anergy, and senescence entail separate and distinct entities of dysfunction, though all are typically characterized by decreased effector function or proliferation. In this review, we seek to define these distinct spheres of NK cell dysfunction, analyzing how they have been shown to impact NK biology and clinical applications, and ultimately highlight key characteristics in NK cell function, particularly in relation to the role of "exhaustion."
MeSH term(s)	Humans ; Killer Cells, Natural ; Neoplasms
Language	English
Publishing date	2020-02-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2020.00049
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Article ; Online: A possible new pathway in natural killer cell activation also reveals the difficulty in determining human NK cell function in cancer.

Canter, Robert J / Murphy, William J

Journal for immunotherapy of cancer

2018 Volume 6, Issue 1, Page(s) 79

Abstract: Immunotherapy is rapidly becoming the fourth arm of cancer treatment, and breakthrough successes have been observed in multiple malignancies. However, despite the potential for impressive anti-tumor effects, on average, only 25% of patients respond, and ... ...

Abstract	Immunotherapy is rapidly becoming the fourth arm of cancer treatment, and breakthrough successes have been observed in multiple malignancies. However, despite the potential for impressive anti-tumor effects, on average, only 25% of patients respond, and barriers clearly remain. Hence, uncovering innovative ways to apply immunotherapy and overcome immune resistance remains an unmet need in immuno-oncology. Natural killer (NK) cells are an attractive candidate for extending the promise of immunotherapy, although success to date has been largely limited to hematological cancers. An important study has identified novel ways in which NK cells sense and respond to tumors, and these findings may impact clinical translation of NK cells in cancer immunotherapy. Using the activating receptor NKp44, NK cells were shown to bind platelet-derived growth factor DD (PDGF-DD) which was secreted by tumors. Using transgenic mice, NKp44 binding of tumor-expressed PDGF-DD was able to limit tumor growth, and expression of natural cytotoxicity receptor-associated gene signatures (of which NKp44 is a member) was correlated to clinical outcomes. This study highlights the potential for effector-target interactions to impact immune homeostasis in previously unrecognized ways, while at the same time, underscoring the complexities inherent in pre-clinical/ translational experimental design which may confound clinical application of these interesting results.
MeSH term(s)	Animals ; Cells, Cultured ; Humans ; Immunotherapy ; Killer Cells, Natural/immunology ; Lymphocyte Activation ; Mice ; Neoplasms
Language	English
Publishing date	2018-08-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1186/s40425-018-0392-0
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