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.
Authors: Sorski L. , Melamed R. , Levi B. , Matzner P. , Lavon H. , Rosenne E. , Shaashua L. , Ricon I. , Sandbank E. , Benbenishty A. , et al. .
Source: Cancer Immunology, Immunotherapy : Cii, 2020-05-13 00:00:00.0; , .
EPub date: 2020-05-13 00:00:00.0.
PMID: 32405793
Related Citations

Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling.
Authors: Ricon I. , Hanalis-Miller T. , Haldar R. , Jacoby R. , Ben-Eliyahu S. .
Source: Cancer, 2018-10-06 00:00:00.0; , .
EPub date: 2018-10-06 00:00:00.0.
PMID: 30291805
Related Citations

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 00:00:00.0; 159(1), p. 248-259.
PMID: 29059290
Related Citations

Reducing Liver Metastases Of Colon Cancer In The Context Of Extensive And Minor Surgeries Through ¿-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.
PMID: 27235931
Related Citations

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. 209-20.
PMID: 26944000
Related Citations

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 00:00:00.0; 138(7), p. 1754-64.
EPub date: 2016-04-01 00:00:00.0.
PMID: 26453448
Related Citations

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.
PMID: 24190423
Related Citations

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.
PMID: 24636497
Related Citations

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.
PMID: 24333572
Related Citations

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
Related Citations

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.
PMID: 22504092
Related Citations

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.
PMID: 23153554
Related Citations

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 00:00:00.0; 18(18), p. 4895-902.
PMID: 22753587
Related Citations

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.
PMID: 22659252
Related Citations

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.
PMID: 22122868
Related Citations

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.
PMID: 21963875
Related Citations

The Effect Of ¿-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.
PMID: 21888867
Related Citations

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.
PMID: 21277367
Related Citations

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.
PMID: 21475023
Related Citations

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.
PMID: 20656015
Related Citations

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; 6(4), p. e19246.
PMID: 21559428
Related Citations

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.
PMID: 20362661
Related Citations

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 00:00:00.0; 184(5), p. 2449-57.
PMID: 20124103
Related Citations

The Marginating-pulmonary Immune Compartment In Rats: Characteristics Of Continuous Inflammation And Activated Nk Cells
Authors: Melamed R. , Rosenne E. , Benish M. , Goldfarb Y. , Levi B. , Ben-Eliyahu S. .
Source: Journal Of Immunotherapy (hagerstown, Md. : 1997), 2010 Jan; 33(1), p. 16-29.
PMID: 19952959
Related Citations

Metastatic-promoting Effects Of Lps: Sexual Dimorphism And Mediation By Catecholamines And Prostaglandins
Authors: Naor R. , Domankevich V. , Shemer S. , Sominsky L. , Rosenne E. , Levi B. , Ben-Eliyahu S. .
Source: Brain, Behavior, And Immunity, 2009 Jul; 23(5), p. 611-21.
PMID: 18951972
Related Citations

Cpg-c Oligodeoxynucleotides Limit The Deleterious Effects Of Beta-adrenoceptor Stimulation On Nk Cytotoxicity And Metastatic Dissemination
Authors: Goldfarb Y. , Benish M. , Rosenne E. , Melamed R. , Levi B. , Glasner A. , Ben-Eliyahu S. .
Source: Journal Of Immunotherapy (hagerstown, Md. : 1997), 2009 Apr; 32(3), p. 280-91.
PMID: 19242372
Related Citations

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.
PMID: 19034095
Related Citations

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.
PMID: 18398660
Related Citations