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Grant Details

Grant Number: 5R01CA125456-05 Interpret this number
Primary Investigator: Ben-Eliyahu, Shamgar
Organization: Tel Aviv University
Project Title: Psychoneuroimmunology-Immunotherapy Interactions
Fiscal Year: 2011


DESCRIPTION (provided by applicant): Immuno-stimulatory (IS) therapy in cancer patients is often more effective when combined with other interventions, and when limiting mechanisms are deactivated. Various stressors, neuroendocrine responses, and cytokines are known to modulate immune competence, and can thus modulate responses to IS agents and potentially dampen their therapeutic efficacy. Here we aim at studying potential interactions between psycho-neuro-immunological (PNI) processes and IS treatments, with the intention of unraveling underlying mechanisms, and potentiating immunotherapy. Our studies will revolve around three interrelated interactions: (1) Psychological stress before and during IS therapy is common in cancer patients, but is rarely simulated in animal models of immunotherapy. Stress responses often reduce TH1 and promote proinflammatory responses, potentially dampening beneficial impact of IS agents and worsening their side effects. (2) The host physiological response to IS agents includes perturbations in cytokines and stress hormones that can suppress cell mediated immunity (CMI) (see Preliminary Studies) and self-limit the efficacy of IS approaches. (3) At critical times, including the immediate post-operative period, successful IS approaches could be rendered ineffective by the clinically well-established suppression of CMI following major surgeries. Supplementing IS approaches with our recently developed PNI-based pharmacological interventions (see Preliminary Studies) can prevent such immune suppression, thus preserving the potential benefits of IS approaches. We propose to study and improve the efficacy of three immunostimulatory agents, IL-12, poly I-C, and CpG oligodeoxynucleotides (ODN), under ongoing social stress conditions and following surgery. Outcomes will include NK activation markers and cytotoxicity, cytokine levels and their induced production, and in vivo resistance to experimental and spontaneous metastasis in rodents (MADB106, B16, and 3LL tumors). Neuroendocrine and cytokine mediators of the deleterious effects of stress and of IS agents will be studied. Integrated protocols of immune stimulation and pharmacological blockade of deleterious stress and cytokine responses will be developed and used during stress, IS treatment, and surgery. The knowledge gained could reduce side effects and enhance the efficacy of immunotherapy before and after surgery, potentially increasing survival rates in cancer patients.


Prevention of liver metastases through perioperative acute CpG-C immune stimulation.
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Source: Cancer immunology, immunotherapy : CII, 2020 Oct; 69(10), p. 2021-2031.
EPub date: 2020-05-13.
PMID: 32405793
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Regeneration of Functional Adrenal Tissue Following Bilateral Adrenalectomy.
Authors: Gotlieb N. , Albaz E. , Shaashua L. , Sorski L. , Matzner P. , Rosenne E. , Amram B. , Benbenishty A. , Golomb E. , Ben-Eliyahu S. .
Source: Endocrinology, 2018-01-01; 159(1), p. 248-259.
PMID: 29059290
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Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through β-adrenoceptors blockade and COX2 inhibition.
Authors: Sorski L. , Melamed R. , Matzner P. , Lavon H. , Shaashua L. , Rosenne E. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2016 Nov; 58, p. 91-98.
EPub date: 2016-05-25.
PMID: 27235931
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Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period.
Authors: Levi B. , Matzner P. , Goldfarb Y. , Sorski L. , Shaashua L. , Melamed R. , Rosenne E. , Page G.G. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2016 Aug; 56, p. 209-220.
EPub date: 2016-03-02.
PMID: 26944000
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Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects.
Authors: Matzner P. , Sorski L. , Shaashua L. , Elbaz E. , Lavon H. , Melamed R. , Rosenne E. , Gotlieb N. , Benbenishty A. , Reed S.G. , et al. .
Source: International journal of cancer, 2016-04-01; 138(7), p. 1754-64.
EPub date: 2015-10-26.
PMID: 26453448
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Impact of surgical extent and sex on the hepatic metastasis of colon cancer.
Authors: Sorski L. , Levi B. , Shaashua L. , Neeman E. , Benish M. , Matzner P. , Hoffman A. , Ben-Eliyahu S. .
Source: Surgery today, 2014 Oct; 44(10), p. 1925-34.
EPub date: 2013-11-06.
PMID: 24190423
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Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not catecholamines or opioids.
Authors: Shaashua L. , Rosenne E. , Neeman E. , Sorski L. , Sominsky L. , Matzner P. , Page G.G. , Ben-Eliyahu S. .
Source: Psychoneuroendocrinology, 2014 Apr; 42, p. 11-23.
EPub date: 2014-01-07.
PMID: 24636497
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In vivo suppression of NK cell cytotoxicity by stress and surgery: glucocorticoids have a minor role compared to catecholamines and prostaglandins.
Authors: Rosenne E. , Sorski L. , Shaashua L. , Neeman E. , Matzner P. , Levi B. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2014 Mar; 37, p. 207-19.
EPub date: 2013-12-12.
PMID: 24333572
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The marginating-pulmonary immune compartment in mice exhibits increased NK cytotoxicity and unique cellular characteristics.
Authors: Benish M. , Melamed R. , Rosenne E. , Neeman E. , Sorski L. , Levi B. , Shaashua L. , Matzner P. , Ben-Eliyahu S. .
Source: Immunologic research, 2014 Jan; 58(1), p. 28-39.
PMID: 24132552
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Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement.
Authors: Neeman E. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2013 Mar; 30 Suppl, p. S32-40.
EPub date: 2012-04-04.
PMID: 22504092
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PGE2 suppresses NK activity in vivo directly and through adrenal hormones: effects that cannot be reflected by ex vivo assessment of NK cytotoxicity.
Authors: Meron G. , Tishler Y. , Shaashua L. , Rosenne E. , Levi B. , Melamed R. , Gotlieb N. , Matzner P. , Sorski L. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2013 Feb; 28, p. 128-38.
EPub date: 2012-11-12.
PMID: 23153554
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A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins.
Authors: Neeman E. , Zmora O. , Ben-Eliyahu S. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2012-09-15; 18(18), p. 4895-902.
EPub date: 2012-07-02.
PMID: 22753587
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In vivo suppression of plasma IL-12 levels by acute and chronic stress paradigms: potential mediating mechanisms and sex differences.
Authors: Shaashua L. , Sominsky L. , Levi B. , Sorski L. , Reznick M. , Page G.G. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2012 Aug; 26(6), p. 996-1005.
EPub date: 2012-05-29.
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Fish oil attenuates surgery-induced immunosuppression, limits post-operative metastatic dissemination and increases long-term recurrence-free survival in rodents inoculated with cancer cells.
Authors: Goldfarb Y. , Shapiro H. , Singer P. , Kalderon Y. , Levi B. , Glasner A. , Benish M. , Ben-Eliyahu S. .
Source: Clinical nutrition (Edinburgh, Scotland), 2012 Jun; 31(3), p. 396-404.
EPub date: 2011-11-26.
PMID: 22122868
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Stress and skin leukocyte trafficking as a dual-stage process.
Authors: Neeman E. , Shaashua L. , Benish M. , Page G.G. , Zmora O. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2012 Feb; 26(2), p. 267-76.
EPub date: 2011-09-19.
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The effect of β-adrenergic blockade and COX-2 inhibition on healing of colon, muscle, and skin in rats undergoing colonic anastomosis.
Authors: Hazut O. , Shaashua L. , Benish M. , Levi B. , Sorski L. , Benjamin B. , Hoffman A. , Zmora O. , Ben-Eliyahu S. .
Source: International journal of clinical pharmacology and therapeutics, 2011 Sep; 49(9), p. 545-54.
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Continuous stress disrupts immunostimulatory effects of IL-12.
Authors: Levi B. , Benish M. , Goldfarb Y. , Sorski L. , Melamed R. , Rosenne E. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2011 May; 25(4), p. 727-35.
EPub date: 2011-01-28.
PMID: 21277367
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Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity.
Authors: Inbar S. , Neeman E. , Avraham R. , Benish M. , Rosenne E. , Ben-Eliyahu S. .
Source: PloS one, 2011-04-29; 6(4), p. e19246.
EPub date: 2011-04-29.
PMID: 21559428
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Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses.
Authors: Goldfarb Y. , Sorski L. , Benish M. , Levi B. , Melamed R. , Ben-Eliyahu S. .
Source: Annals of surgery, 2011 Apr; 253(4), p. 798-810.
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CpG-C immunotherapeutic efficacy is jeopardized by ongoing exposure to stress: potential implications for clinical use.
Authors: Goldfarb Y. , Levi B. , Sorski L. , Frenkel D. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2011 Jan; 25(1), p. 67-76.
EPub date: 2010-07-23.
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Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression.
Authors: Avraham R. , Benish M. , Inbar S. , Bartal I. , Rosenne E. , Ben-Eliyahu S. .
Source: Brain, behavior, and immunity, 2010 Aug; 24(6), p. 952-8.
EPub date: 2010-03-31.
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Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor.
Authors: Glasner A. , Avraham R. , Rosenne E. , Benish M. , Zmora O. , Shemer S. , Meiboom H. , Ben-Eliyahu S. .
Source: Journal of immunology (Baltimore, Md. : 1950), 2010-03-01; 184(5), p. 2449-57.
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Metastatic-promoting effects of LPS: sexual dimorphism and mediation by catecholamines and prostaglandins.
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Source: Brain, behavior, and immunity, 2009 Jul; 23(5), p. 611-21.
EPub date: 2008-10-08.
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CpG-C oligodeoxynucleotides limit the deleterious effects of beta-adrenoceptor stimulation on NK cytotoxicity and metastatic dissemination.
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Blood transfusion promotes cancer progression: a critical role for aged erythrocytes.
Authors: Atzil S. , Arad M. , Glasner A. , Abiri N. , Avraham R. , Greenfeld K. , Rosenne E. , Beilin B. , Ben-Eliyahu S. .
Source: Anesthesiology, 2008 Dec; 109(6), p. 989-97.
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Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis.
Authors: Benish M. , Bartal I. , Goldfarb Y. , Levi B. , Avraham R. , Raz A. , Ben-Eliyahu S. .
Source: Annals of surgical oncology, 2008 Jul; 15(7), p. 2042-52.
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