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Future Health Summit
LOW DOSE CYTOKINES IN SUPPORTIVE THERAPY FOR CANCER
From research: Up to date pre-clinical evidence
*...
Low Dose Medicine into the Universities
MASTER BIENNALE DI II LIVELLO
LOW DOSE MEDICINE IN
PSICO-NERUO-ENDOCRINO-
IMMUNOLO...
LOW DOSE MEDICINE
Low Dose Medicine integrates state of the art scientific
advances in:
P.N.E.I.
Molecular
Biology
Nano-
P...
BIO-
REGULATING
PHYSIOLOGY
LOW DOSE
CYTOKINES
LOW DOSE
NEURO
PEPTIDES
LOW DOSE
HORMONES
LOW DOSE
GROWTH
FACTORS
LOW DOSE M...
CENTRAL NERVOUS SYSTEM
&
AUTONOMIC SYSTEM
IMMUNE SYSTEM
ENDOCRINE SYSTEM
HOMEOSTATIC Control Systems and
bi-directional cr...
STRESS AXIS
Th1
Th2
Reduction of
IFN-γ
X
CD8+
Tc
Not correct
stimulation of
Ts
© Dipartimento Scientifico Guna S.p.a.
•Coh...
AN ALTERATED CROSS-TALK DUE TO AN
UNBALANCE* BETWEEN SIGNALING MOLECULES
PLAYS A CRUCIAL ROLE IN THE ONSET OF
INFLAMMATORY...
HEALTH
PHYSIOLOGICAL CONCENTRATION
DISEASE
DISEASE
HYPO-CONCENTRATION
HYPER-CONCENTRATION10-6
10-15
C O P E
Cytokines & Ce...
g (gram)= 1
10 -1 = 0.1
10 -2 = 0.01
mg (milligram)= 10 -3 = 0.001
μg (microgram)= 10 -6 = 0.000001
ng (nanogram)= 10 -9 =...
The membrane receptor plays a KEY role.
ONLY physiological concentrations are able to
activate or reactivate the membrane ...
CENTRAL NERVOUS SYSTEM
&
AUTONOMIC SYSTEM
IMMUNE SYSTEM
ENDOCRINE SYSTEM
HOMEOSTATIC Control Systems and
bi-directional cr...
16
Th-1/Th-2 BALANCE
Th2
Crohn’s Disease
Psoriasis
Vitiligo
…
Asthma
Atopy
…
Th1
TReg
Th1 UP-REGULATION
Th2 DOWN-REGULATIO...
HEALTH
HYPER
HYPO
Cytokines UP
• IL-1
• IL-6
• TNF-α
• IL-17
• INF-γ
• IL-2
• IL-8
Cytokines DOWN
• TGF-β
• IL-4
• IL-10
C...
Raphael I et al. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine (2014),
ht...
PROBLEM
Is it possible to modulate the
action of cytokines and other
signaling molecules?
IF DISEASES ARE EXPRESSIONS, CON...
Antagonistic cytokines are utilized in order
to slow down a biological effect; Same
cytokines in order to enhance a biolog...
Th0
Th2Th1
IL-12, INF-γ IL-4
INF-γ DOWN-REGULATES
IL-12 UP-REGULATES
IL-4 UP-REGULATES
IL-4 DOWN-REGULATES
Th subsets cros...
©DipartimentoScientificoGunaS.p.a.
IL-10 4C
A novel, systemic,
integrated,
synergistic approach for
supportive therapy in
Cancer
© Dipartimento Scientifico Guna S.p.a.
© Dipartimento Scientifico Guna S.p.a.
D’Amico L, Ruffini E, Ferracini R, Roato I (2012) Low Dose
of IL-12 stimulates T Ce...
Th0
Th2Th1
TReg
TGF-β
DOWN-REGULATES DOWN-REGULATES
Plasticity and Rigidity of
Relationship among Th1-Th2-Th3
© Dipartimen...
© Dipartimento Scientifico Guna S.p.a.
1.7 1.7
0.9
4.5
0.8
0.6
0.4
1.8
0.2
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
basale CH3 CH4 ...
basale CH3 CH4 placebo IL12 10 ng/ml
Series1 30.7 19 48.4 48.3 4.8
0
10
20
30
40
50
60
%CD4/IFNgamma Day 5
CH3 CH4 placebo...
© Dipartimento Scientifico Guna S.p.a.
Legenda:
•Left column =
not-treated control group
•Central column =
patients treated with
conventional dosage of
IFN-gamma...
Radice E, Bellone G, Miranda V.
Enhancement of the immunomodulatory functions of ex vivo-generated dendritic cells from ea...
The aim of this study is to assess in vitro the ability of single or
sequentially combined exposure to very low doses of S...
EX VIVO STUDY
16 subjects
(10 males, 6 females; mean age 73; range 57-83)
With colon carcinoma
16
9 primary colon
carcinom...
EX VIVO STUDY
INCLUSION CRITERIA
• Subjects affected by primary colon carcinoma needing surgery without
pre-surgery eviden...
Translational Oncology 2015 8, 327-338DOI: (10.1016/j.tranon.2015.06.005)
(A) MoDC (monocyte derived denditic cells) allos...
Translational Oncology 2015 8, 327-338DOI: (10.1016/j.tranon.2015.06.005)
.
Effects of standard-dose rhIL-4 and/or rhIL-12...
IL-4 (10 fg/ml SKA) IL-12 (10 fg/ml SKA)
IFN-g (10 fg/ml SKA)
IL-12 (10 fg/ml SKA)
GUNA IMMUNITY SYSTEM ACTIVATION IN CANC...
Biomedico
www.biomedico.ie
sales@biomedico.ie
Facebook: biomedico
Tel: 0873275484 - 0874102519
37
FOR FURTHER INFORMATION
...
Dr Alessandro Perra , Guna S,p.a.Italy
Dr Alessandro Perra , Guna S,p.a.Italy
Dr Alessandro Perra , Guna S,p.a.Italy
Dr Alessandro Perra , Guna S,p.a.Italy
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Dr Alessandro Perra , Guna S,p.a.Italy

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Low Dose Cytokines in supportive therapy for cancer

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Dr Alessandro Perra , Guna S,p.a.Italy

  1. 1. Future Health Summit LOW DOSE CYTOKINES IN SUPPORTIVE THERAPY FOR CANCER From research: Up to date pre-clinical evidence ***** DUBLIN May 26th, 2016 Alessandro Perra – Scientific Director of GUNA S.p.a.
  2. 2. Low Dose Medicine into the Universities MASTER BIENNALE DI II LIVELLO LOW DOSE MEDICINE IN PSICO-NERUO-ENDOCRINO- IMMUNOLOGIA Applicazioni in Medicina Generale, nelle Disfunzioni Neuro-Muscolo-Scheletriche e nell’ Healthy Aging © Dipartimento Scientifico Guna S.p.a.
  3. 3. LOW DOSE MEDICINE Low Dose Medicine integrates state of the art scientific advances in: P.N.E.I. Molecular Biology Nano- Pharmacology linked to Quantum Physics © Dipartimento Scientifico Guna S.p.a.
  4. 4. BIO- REGULATING PHYSIOLOGY LOW DOSE CYTOKINES LOW DOSE NEURO PEPTIDES LOW DOSE HORMONES LOW DOSE GROWTH FACTORS LOW DOSE MEDICINE A NOVEL, INTEGRATED, SYSTEMIC APPROACH TO DISEASES © Dipartimento Scientifico Guna S.p.a.
  5. 5. CENTRAL NERVOUS SYSTEM & AUTONOMIC SYSTEM IMMUNE SYSTEM ENDOCRINE SYSTEM HOMEOSTATIC Control Systems and bi-directional cross-talk Ader, R., Psychoneuroimmunology, IV edition, vol. 1 e 2, Academic Press, Amsterdam 2007. It is the classical text on the matter, pubblished for the first time in 1981. P N E I © Dipartimento Scientifico Guna S.p.a.
  6. 6. STRESS AXIS Th1 Th2 Reduction of IFN-γ X CD8+ Tc Not correct stimulation of Ts © Dipartimento Scientifico Guna S.p.a. •Cohen M, et al. Increased emotional distress in daughters of breast cancer patients is associated with decreased natural cytotoxic activity, elevated levels of stress hormones and decreased secretion of Th1 cytokines. Int J Cancer. 2002;100(3):347-54. •Montoro J, et al. Stress and allergy. J Investig Allergol Clin Immunol. 2009;19 Suppl 1:40-7. •He Y, et al. Psychological stress exerts effects on pathogenesis of hepatitis B via type-1/type-2 cytokines shift toward type-2 cytokine response. PLoS One. 2014;9(8):e105530. •Radice E, et al. Low-doses of sequential-kinetic-activated interferon-gamma enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study Intern. Immunopharm 2014;19:66-73. DOWN-REGULATION OF Th1
  7. 7. AN ALTERATED CROSS-TALK DUE TO AN UNBALANCE* BETWEEN SIGNALING MOLECULES PLAYS A CRUCIAL ROLE IN THE ONSET OF INFLAMMATORY, ALLERGIC AND AUTO-IMMUNE DISEASES *ALTERATED CONCENTRATIONS P.N.E.I. NETWORK AND SIGNALING MOLECULES © Dipartimento Scientifico Guna S.p.a.
  8. 8. HEALTH PHYSIOLOGICAL CONCENTRATION DISEASE DISEASE HYPO-CONCENTRATION HYPER-CONCENTRATION10-6 10-15 C O P E Cytokines & Cells Online Pathfinder Encyclopedia Version 26.7 (Spring 2011 Edition) © Dipartimento Scientifico Guna S.p.a.
  9. 9. g (gram)= 1 10 -1 = 0.1 10 -2 = 0.01 mg (milligram)= 10 -3 = 0.001 μg (microgram)= 10 -6 = 0.000001 ng (nanogram)= 10 -9 = 0.000000001 pcg (picogram)= 10 -12 = 0.000000000001 fg (fentogram)= 10 -15 = 0.000000000000001 DEFINITIONS © Dipartimento Scientifico Guna S.p.a.
  10. 10. The membrane receptor plays a KEY role. ONLY physiological concentrations are able to activate or reactivate the membrane receptors and consequently, stimulate the physiological function of a target cell. 14 UP- AND DOWN-REGULATION - Akahoshi T et al. Interleukin 1 stimulates its own receptor expression on human fibroblasts through the endogenous production of prostaglandin(s). J Clin Invest. 1988 Oct;82(4):1219-24 - Samanta AK et al. Interleukin 8 (monocyte-derived neutrophil chemotactic factor) dynamically regulates its own receptor expression on human neutrophils. J Biol Chem. 1990 Jan 5;265(1):183-9. © Dipartimento Scientifico Guna S.p.a.
  11. 11. CENTRAL NERVOUS SYSTEM & AUTONOMIC SYSTEM IMMUNE SYSTEM ENDOCRINE SYSTEM HOMEOSTATIC Control Systems and bi-directional cross-talk Ader, R., Psychoneuroimmunology, IV edition, vol. 1 e 2, Academic Press, Amsterdam 2007. It is the classical text on the matter, pubblished for the first time in 1981. P N E I © Dipartimento Scientifico Guna S.p.a.
  12. 12. 16 Th-1/Th-2 BALANCE Th2 Crohn’s Disease Psoriasis Vitiligo … Asthma Atopy … Th1 TReg Th1 UP-REGULATION Th2 DOWN-REGULATION Th1 DOWN-REGULATION Th2 UP-REGULATION Th2 Th1 Th17 © Dipartimento Scientifico Guna S.p.a.
  13. 13. HEALTH HYPER HYPO Cytokines UP • IL-1 • IL-6 • TNF-α • IL-17 • INF-γ • IL-2 • IL-8 Cytokines DOWN • TGF-β • IL-4 • IL-10 Cytokines DOWN • IL-1 • IL-6 • TNF-α • IL-17 • INF-γ • IL-2 • IL-8 Cytokines UP • TGF-β • IL-4 • IL-10 Physiological concentration • IL-1 • IL-6 • TNF-α • IL-17 • INF-γ • IL-2 • IL-8 Physiological concentration • TGF-β • IL-4 • IL-10 © Dipartimento Scientifico Guna S.p.a.
  14. 14. Raphael I et al. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine (2014), http://dx.doi.org/10.1016/j.cyto.2014.09.011 Neither good nor bad in Nature
  15. 15. PROBLEM Is it possible to modulate the action of cytokines and other signaling molecules? IF DISEASES ARE EXPRESSIONS, CONSEQUENCES OF CHANGED CONCENTRATION OF MESSENGER MOLECULES… © Dipartimento Scientifico Guna S.p.a.
  16. 16. Antagonistic cytokines are utilized in order to slow down a biological effect; Same cytokines in order to enhance a biological function. The concept of BALANCE and the use of SKA low dose cytokines © Dipartimento Scientifico Guna S.p.a.
  17. 17. Th0 Th2Th1 IL-12, INF-γ IL-4 INF-γ DOWN-REGULATES IL-12 UP-REGULATES IL-4 UP-REGULATES IL-4 DOWN-REGULATES Th subsets cross-regulate expansion and functions each other. - Cooke , A. Th17 in Inflammatory Conditions. 2006, Rev Diabetic Stud 3: 72-7 - Bettelli E. et al. Th17: the third member of the effector T cell trilogy. Current Opinion in Immunology 2007, 19: 652-657 Inflammatory diseases Allergy THE CONCEPT OF BALANCE – RECIPROCITY of TH CELLS © Dipartimento Scientifico Guna S.p.a.
  18. 18. ©DipartimentoScientificoGunaS.p.a. IL-10 4C
  19. 19. A novel, systemic, integrated, synergistic approach for supportive therapy in Cancer © Dipartimento Scientifico Guna S.p.a.
  20. 20. © Dipartimento Scientifico Guna S.p.a. D’Amico L, Ruffini E, Ferracini R, Roato I (2012) Low Dose of IL-12 stimulates T Cell response in cultures of PBMCs derived from Non Small Cell Lung Cancer Patients. Journal of Cancer Therapy 3: 337-342.
  21. 21. Th0 Th2Th1 TReg TGF-β DOWN-REGULATES DOWN-REGULATES Plasticity and Rigidity of Relationship among Th1-Th2-Th3 © Dipartimento Scientifico Guna S.p.a.
  22. 22. © Dipartimento Scientifico Guna S.p.a. 1.7 1.7 0.9 4.5 0.8 0.6 0.4 1.8 0.2 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 basale CH3 CH4 placebo IL12 10ng/ml CD4/Treg day 5 day 10 healthy ctrl 1pg/ml 0.01pg/ml SKA basal 10 ng/ml
  23. 23. basale CH3 CH4 placebo IL12 10 ng/ml Series1 30.7 19 48.4 48.3 4.8 0 10 20 30 40 50 60 %CD4/IFNgamma Day 5 CH3 CH4 placebo IL12 10 ng/ml Series1 32.8 56 46.2 4.2 0 10 20 30 40 50 60 %CD4/IFNgamma Day 10 © Dipartimento Scientifico Guna S.p.a. IL-12 0.01pg/ml SKAIL-12 1pg/ml SKA
  24. 24. © Dipartimento Scientifico Guna S.p.a.
  25. 25. Legenda: •Left column = not-treated control group •Central column = patients treated with conventional dosage of IFN-gamma (1 ng/ml) •Right column = patients treated with IFN-gamma GUNA (0.25 fg/ml) Healthy subjects Non- metastatic cancer patients Metastatic cancer patientsHealthy subjects Non metastatic cancer patients Metastatic cancer patients © Dipartimento Scientifico Guna S.p.a.
  26. 26. Radice E, Bellone G, Miranda V. Enhancement of the immunomodulatory functions of ex vivo-generated dendritic cells from early- stage colon cancer patients by consecutive exposure to low doses of sequential kinetic activated IL-4 and IL-12. A preliminary study. Translational Oncology 2015;8:327-38 © Dipartimento Scientifico Guna S.p.a.
  27. 27. The aim of this study is to assess in vitro the ability of single or sequentially combined exposure to very low doses of SKA IL-4 and IL-12 (10-8 µg/ml) to enhance DCs’ antigen presentation capacity compared to the normally administered doses of recombinant human (rh) IL-4 and IL-12. Ex vivo study on dendritic cells obtained from the peripheral blood of patients with early stage colorectal carcinoma (CRC) - in the presence or absence of metastasis - and from healthy donors. STUDY TYPE AIM OF THE STUDY © Dipartimento Scientifico Guna S.p.a.
  28. 28. EX VIVO STUDY 16 subjects (10 males, 6 females; mean age 73; range 57-83) With colon carcinoma 16 9 primary colon carcinoma 2 Dukes A 7 Dukes B 1-2 7 metastatic colon carcinoma Dukes C 1-2 with lymph node metastasis 12 subjects (7 males, 5 females; mean age 64; range 37-85) Healthy donors
  29. 29. EX VIVO STUDY INCLUSION CRITERIA • Subjects affected by primary colon carcinoma needing surgery without pre-surgery evidence of distance metatstasis a PREPARATIONS • SKA-IL-4 (10 fg/ml) GUNA Laboratories • SKA-IL-12 (10 fg/ml) GUNA Laboratories • rhIL-4 (1ng/ml) Pepro Tech Inc. • rhIL-12 (1ng/ml) Pepro Tech Inc.
  30. 30. Translational Oncology 2015 8, 327-338DOI: (10.1016/j.tranon.2015.06.005) (A) MoDC (monocyte derived denditic cells) allostimulatory activity of colon carcinoma patients (n = 16) versus healthy donors (n = 12). (B) MoDC allostimulatory activity of nonmetastatic (n = 9) versus metastatic (n = 7) colon carcinoma patients. MoDCs, generated by culturing PB CD14+ cells from tumor and normal subjects in the presence of rhGM-CSF and rhIL-4 for 6 days, were incubated with 1 × 105 allogeneic naïve CD4+ T cells at 1:40, 1:20, and 1:10 ratios for 5 days followed by a 6-hour pulse of 3 H-TdR. Results are expressed as mean ± SE cpm of triplicate co- cultures. Statistical significance was determined using one-way ANOVA. RESULTS
  31. 31. Translational Oncology 2015 8, 327-338DOI: (10.1016/j.tranon.2015.06.005) . Effects of standard-dose rhIL-4 and/or rhIL-12 and low- dose SKA-IL-4 and/or SKA-IL-12 on APC activity in MLR of MoDCs from nonmetastatic colon carcinoma patients (n = 6) and from metastatic colon carcinoma patients (n = 7). MoDCs were untreated or pretreated with SKA-IL-4 (48 hours) and SKA-IL-12 (24 hours) as single agents or sequentially in parallel to the rh cytokines, and subjected to MLR with allogeneic naïve T cells in different MoDC-to- T cell ratios. The figure shows the mean percentages ± SE of 3H-TdR incorporation in cpm. Statistical significance was determined using one-way ANOVA. Rh/SKA cytokine pretreated nonmetastatic/metastatic colon carcinoma MoDCs versus untreated nonmetastatic/metastatic colon carcinoma MoDCs: *P < .05 and **P < .01. Nonmetastatic colon carcinoma MoDCs versus metastatic colon carcinoma MoDCs: ●● P < .01 and ●●● P < .0001. RESULTS* RECOMBINANT HIGH DOSE LOW DOSE SKA
  32. 32. IL-4 (10 fg/ml SKA) IL-12 (10 fg/ml SKA) IFN-g (10 fg/ml SKA) IL-12 (10 fg/ml SKA) GUNA IMMUNITY SYSTEM ACTIVATION IN CANCER
  33. 33. Biomedico www.biomedico.ie sales@biomedico.ie Facebook: biomedico Tel: 0873275484 - 0874102519 37 FOR FURTHER INFORMATION © Dipartimento Scientifico Guna S.p.a.

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