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Prof. T. Hajtó: - Medical University Pécs /Hungary

Prof. T. Hajtó: - Medical University Pécs /Hungary Containing PAMP like Arabinoxylan molecules i s BioBran the best standardized immunomodulator which can be used in the tumour therapy ?. HEALING POWER OF THE NATURE.

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Prof. T. Hajtó: - Medical University Pécs /Hungary

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  1. Prof. T. Hajtó: - Medical University Pécs /Hungary ContainingPAMP likeArabinoxylanmolecules is BioBranthebeststandardizedimmunomodulatorwhichcan be used in thetumourtherapy?

  2. HEALING POWER OF THE NATURE Yasuo Ninomiya, the founder of Daiwa Pharmaceutical which produces Biobran said: ‟We believe that it is of the utmost importance to trust in nature, with which we must co-exist. We believe that the body’s natural healing power provides the foundation necessary to correct physical imbalances.”

  3. More than 20 yearsagoitwasshownthatstandardizedbranriceextractsactivate NK cells Natural killer cells (Large Granular Lymphocytes) for monitoring of the natural immune defence .Dr.Hiroaki Maeda, Head of Research and Development at Daiwa Dr.Ghoneuman immunologist at the University of California in Los Angeles, USA.

  4. More than 20 years ago: ADORATION of T LYMPHOCYTES T cells recognizes 10 15 EPITOPES on surface of TU cells.NK cells recognize only stress related molecules on TU cells with limited specificity. It is not the firstserious error of TUresearch.Now 20 yearslater this laughis stopped.WHY ? Szöveg

  5. ártalmai. Tumour-associated Ag-stogether withotherself proteinsareregu- larlybroken down in proteosome producingtwomillion peptids pro second. Theyarepresented for CD8-T lymphocytes by MHC-I Ag-swhich areregularlyproduced in endoplasmicreticu- lum (with 150 000/sec velocity) butonly 150/sec cangettothecellsurface. -

  6. Twenty years ago Enthusiasm: T cells recognize 1015-1016 epitopes TODAY It is well documented that cancer cells are very often characterized by loss or down regulation of MHC-class-I molecules which are not reversible and not reparable. It leads to a definitive escape of tumour cells from T cell lyse.

  7. New clinicaleffortstoinhibitthenegativeco-stimulatorysignals (suchas PD1-PDL-1 and 2 aswellas CD80/CD86 and CTLA-4) toimprove T cellactivation /Neg. signals /-----------positiveco-stimulatorysignals--------------/ Nivolumab –Opdivo There is a significant clinicalbenefit in melanoma and cancer of kidney PROBLEM: Quantitativeloss + qualitativechange of MHC-I -

  8. INNATE IMMUNE SYSTEM Consequently, again and again growing attention is focusing on theeffector cells of innate immune system which are able to kill tumor cells in non-MHCrestricted manner. This system exhibits a polarity and a TU- induced disturbed balance. NK cells is only a soldier in the type-1 system. Namely, the innate immune system is committed in two directions and their balance is disturbed:Tumour-induced suppression of Type-1 cells Tumour-induced dominance of Type-2 cells Pioneers of tumour immunology Type-1 Type-2

  9. Tumour-inducedsuppression of Type-1 cellsType-1macrophages (M1) and from the monocytes originating type-1 maturedentriticcells (D1) generate proinflammatory cytokines, IL-12 and activate cytotoxic effector (such as NK and NKT) cells which are potent inhibitors of tumor growth. However, these type-1 cellsaredefective in tumour patients. Type-1 (cellular) Type-2 (humoral)ModeratelymodificatedIllustrationfromJS. Murray[ImmunolToday1998; 19: 157-63].

  10. TUMOUR-INDUCED DOMINANCE OF TYPE-2 NATURAL IMMUNE CELLSAvailable information suggests that tumour-associatedmacrophages belong to the prototypic Type-2 (M2) population. M2 macrophages and thefrom plasmocytoidprecursors originating D2 dentritic cells generate IL-4 and IL-10 which facilitate the generation of Th2 cells and inhibit Th1 cells aswellasthe type-1 natural system. M2 macrophages and D2 dentritic cells affect inflammation, promote cell proliferation by producing growth factors, stimulate angiogenesis and tissue repair. Tumour patients can have up to 40% M2 peripheral monocytes incontrasttohealthy individuals who have only 10%.Type-1 (cellular) Type-2 (humoral) .

  11. Howcanweinvestgatethistumor-inducedsuppression of type-1 cells?Whatcanwedo?In peripheralboodwecandeterminethetumor-induceddecreasesinphagocyticactivity and NK functions.Type-1 (cellular) Type-2 (humoral).

  12. Indeed, ifweinvestigatethephagocyticactivity and NK cells in peripheralblood of tumourpatients, bothparameters in correlationwiththeprogression of thediesasearediminished.

  13. A successfulimmunotherapy must be associatedwith an activation of Type-1 cells and with an inhibitionof type-2 cells.Cellular (Type-1) (Type-2) HumoralToactivatecascadesystem of type 1cellsweneedPAMP moleculestobind PRR onphagocytes.PAMP only inthenature(bacteriaorplants)(no found in hostno producedbychemistry)PRR onmembraneof type-1 phago-cyticcells. Suggestedeffect of lectin (ML) and Arabinoxylan

  14. The firstdiscovered PLANT – PAMP molecule is lectinfrommistletoeplant. (Now in term of lectinstandardizedmistletoeextractsareonthe market.)Muthing et al. Glycobiology2002; 12: 485-497PAMPPAMP LIGAND = PRR= 2-6 sialyzedneolacto- series ofGANGLIOSIDES .

  15. Similartoconserved PAMP moleculesonmembrane of bacteriathisplantlectinfunctionsalsoas a PAMP moleculebyselectivelybinding of phagocyticcells. After 30 min incubation of FITC labelledlectin molecules in wholeblood Monocytes 99% Granulocytes 99% Lymphocytes <5%

  16. Similartolectin (ML) ARABINOXYLAN CONCENTRATE (BIO-BRAN –MGN-3) has alsoPAMP likeproperties. It isRice branhemicellulosefermentedbymultiplecarbohydrateenzymesfromshiitakemushrooms:Allglykolyticbindingsarebroken down exeptthebindingbetweenarabinoseand xylosewhichresults in an arabinoxylan-concentratewith a retainingitsnaturalconfiguration. The extract (BioBran) is standardizedconcerningitsarabinoxylancontent. Dose: 12-45 mg /kgHighlysafefoodwithoutsideeffect.

  17. A successfulimmunotherapy must be associatedwith an improved immune balance.Arabinoxylansimilartolectin canactivate type-1 naturalimmunecells.Cellular (Type-1) (Type-2) HumoralTwoparameterswhichoftenusedformonitoring the type-1 naturalimmunecells: 1. Phagocyticactivity2. NK activity and level ModeratelymodificatedIllustrationfrom JS. Murray[ImmunolToday 1998; 19: 157-63] Suggestedeffect of lectin (ML) and Arabinoxylan

  18. X (95%CI): 1.04 (0.31) 3.56 (1.33) Ghoneum et al / Hajto et al.phago-cyticactivityNK activity LECTIN ARABINOXYLAN • NaCl LECTIN ARABINOXYLAN

  19. Plant PAMPMoleculesBoth plantlectin andplantarabinoxylancanrepresentstructures (configu-rations) whicharesimilartobacterialPAMP moleculesbutin contrasttobacteriahave no sideeffects. .

  20. . -

  21. .What is theoptimalapplicationscheme of BIOBRAN? BIOBRAN (ARABINOXYLAN) ALONE was given in very various application schemes: the doses varied betwen 5g daily and 1 g daily wihout break or with break of two or three or five days a week.

  22. Atfirst Dr Ghoneumpublishedafterdailyapplicationa permanentinceasingeffecton NK –activity. Resultswithvariouseffector – targetcellratiosafter a treatmentforoneweek, forone and twomonthsareshown. 3 GRAM DAILY Ghoneum M: J Immunother 1998; 14:89-99

  23. Ali K.H. et al.: Functional Foods in Health and Disease 2012;2 (7): 265-279. Fouryearslater Ali et al, investigatedtheeffect of dailyapplicationfor 60 dayson NK activity

  24. The results of Ali is in agreementwiththeobsevations ofChiba University 20 years ago wherethe scientists soconcluded that the effect of Biobran is less if the number of NK cells and their activity is high. S. Bright: Biobran 2017; DHD (EUROPE) LIMITED, organizational 811 03 Bratislava

  25. We must notforgetthatbinding of PRR –moleculesonphagocytescaninduce a caskade-reaction of the Type-1 naturalimmunecells. A permanentstimulationwithlectinwasnotpossible.72h therapy-freeinterval is necessary. .

  26. . SEM:1.9/ 3.6 – 1.0/4.1 - 2.6/4.3 Presentedresults originatefromdfferent methods, a definitiveconclusion is noteasyAftersevendays 53% (ifgivendaily) and 40% (ifgiventwice a week) . Both increasesaresignificant (p<0.05).

  27. Previous cross over investigations with lectin indicated that twice a week may be more effective. Because of synergy we applied twice a week. Mo Tue We Thu Fri Sat Sun __________________________________________________________ Lectin in ME:0.5-1ng/Kg- -0.5-1 ng/kg- - - s.c. s.c. ________________________________________________________ Arabino- 12-45- -12-45- - - xylan in mg/kgmg/kg BioBran p.o. p.o. ________________________________________________________ • Ghoneum M.: Int. J. Immunotherapy • 14(2): 89-99, 1998 • FIRST CONTROLLED • CLINICAL TRIAL 2010

  28. CLINICAL RESULTSA controlledtrialwithArabinoxylanconcentrate (BioBran) is alsoavailableatthemoment. In a three-yearsrandomizedprospectivedoubleblindclinicaltrialArabinoxylanconcentrate(BioBran) wasshowntoenhancetheeffects of interventionalchemotherapyagainsthepatocellularcarcinoma: 1 gr Biobrandailyfor 12 monthsNr. of recidives:31,6% versus 46,7%TU-sizemeasuredbyangiography: 36 % decreaseversus 0.2% decreaseTwoyearssurvival:35% versus 6% . Mai Hong Bang et al.: Anticancer Res 2010; 30: 5145-5152

  29. In spite of factthatArabinoxylan (in BioBran) exhibits a clinicalevidence, the „door of castle” is notopened. No furtherclinicaltrialswerecarried out. The reason is simple: in spite of manyresearch a wellstandardized and evidencebasedphytotherapy is ignoredbythe „GENERAL’ of castle” sinceit is phytotherapy. .

  30. . In Switzerlandwehave an applicationsubmittedtoanethicalcomissiontoget a permissionforacohortclinicaltrialwithstandardizedplantimmunomodulators. Itwasrefused. Onlycasereportswerepermitted. Therefore in thislectureseveralinterestingcasereportswill be presented.

  31. Clinical results 1.) Can the plant PAMP molecules - lead to spontaneous remissions of tumor disease?

  32. Lungmetastasis of a PatientwithLiposarcomaafter animmunomodulatorytherapyfor 13 months had a nearly CR. 20.11.1989 07.02.1990 02.04.1990 26.07.1990 14.09.1990 04.02.1991 Hajto et al. Deutsch. Zschr. Onkol. 1991; 23: 1-6

  33. Clinicalresults . 2.) Can the plant PAMP molecules show clinical benefit if they are combined with conventional chemotherapy?

  34. LIVER-METASTASESAfter a chemotherapy hepatic tumors rarely dissappear completely and the duration of responses is short. Hepatic resection in many cases results in also no long-term benefit. Therefore it was interesting that standardized plant immunomodulators were found to help for induction and for prolongation of complete remissions. Primarytumor OthertherapyImm.Th. Observation Clinicalprogress BreastcancerHormone(Femara) L+B 12 moCR BreastCancerXeloda1500mg/d. L+B 11 monearlyCR ColoncancerAvastin+FOLFIRI L+B 4 moCR ColonCancerOp+FOLFIRI-FOLFOX L+B 31 moCR • Hajto T, Kirsch A. J. Cancer Res Updates 2013; 2: 1-9 Nextpicturespresentsthesecondpatients, who in spite of intensivechemotherapy and surgicaloperation had a very rapid progression.. L=Lectin; B=BioBran

  35. PatientwithLivermetastasestreatedwithLectin+BioBran+lowdose of 5FU Prior tothetreatment Aftertreatmentforthreemonths Aftertreatmentforsevenmonths Hajto T, Kirsch A: J Cancer Res Update 2013; 2:1-9

  36. PatientwithlivermetastasestreatedwithLectin +BioBran+ 5FUAfter7 MoTU-Marker-valuesarenormalized.CEATPA

  37. A 70-year old patient had an inoperable stomach cancer (T3N1Mx). She was treated with pre-adjuvant chemotherapy. After three cycles Epirubicin +Cisplatin+Xeloda without immune therapy in CT investgation no change of her tumour size was found. The following three cycles of chemotherapy (given in the same doses) was combined with standardized plant immunomodulators and this resulted in nearly complete remission. Her body weight increased with 11 kg. She was operable. The little rest of tumor was surgical removed and in the next four years she was tumour-free.

  38. Tumourcandecrease NK functions Because of tumour-inducedsuppressionof type-1 naturalimmunity TODAY Weknowthatthedec- rease of type-1 systemTU-induceddominance of type-2 reducestheexpression of cellsproducingGrowthFactors KAR-receptor (NKG2D) candecreasetheexpression of NK ligands. Oncologicaltreatments in generalshow no beneficialeffect. THERE IS AN EXCEPTION: GEMCITABIN NKG2D MICA MICB ULBP1-3

  39. RECENT RESEARCH RESULTS:Okita R. et al. PLoSOne, 2015 Oct 6.Morisaki T. et al. Anticancer Res 2014; 34(8): 4529-38. • Gemcitabine (Gemzar) caninduce • an enhancedexpression of NKGD2 AfterGemcitabinetreatment • expression of MICA, MICB and • ULBPs(stressrelatedpeptids)upregulated Result: increase in NK activity increase in NK sensitivity of TU cells NKG2D MICA MICB ULBP1+2+3

  40. . 3.Has a combination of plantimmunomodulator-inducedactivationof type-1 cellswithalso NK stimulating GEMCITABINEa clinicalbenefit ? • .

  41. Histologicaldocumentedskinmetastases of a breastcancerpatientshowed a very rapid remissionafter a treatmentwithGemzarand standardizedplantimmunomodulator. Prior tothetherapyAftersixmonths theattendingphysician in theOncologyDepartmentwasnotreadytocontinueit.

  42. Parallel tumourmarkersarealsonormalizedaftersixmonths. CEA CA 15-3

  43. Completeremission of ovariancarcinomaafter a combination of Gemcitabineand plantmmunomodulators A now 46 y old patientwithmetastatized and surgicaloperatedbilateralovariancarcinomaafter 16 cyclesTaxol and Carboplatin had a local recurrence.Thereafter a combination of Gemcitabine(given in lowerdoses) and plantimmunomodulators (lectin + arabinoxylan) induced a completeremission. After 14 monthsshe is tumourfree.

  44. Completeremission of local recurrence of an operatedovariancarcinomaafter a combination of Gemcitabine (given in lowerdoses) and plantimmunomodulators (lectin + arabinoxylan). • . January 2016. May 2017 • Prior thetreatmentAfter 14 months

  45. 4.) Has a combination of immunomodulator-inducedactivation of type-1 cellswithGrowthFactor Receptor (GFR) Inhibitors a clinicalbenefit? IncreasedexpressionImprovement of GrowthFactorby LECTIN and inducedlowexpression of ARABINOXYLAN NK-ligands (stress-related molecules) by GFR inhibitors NKG2D MICA MICB ULBP1+2+3

  46. COMBINATION OF IMMUNOMODULATORS and EGFR-INHIBITOR LUNG ADENOCARCINOMA INOP T3N2M0 beforetreatment Fourmonthslaterafter chemoterapy (4 cycles 300mg Carboplatin and 200mg Taxol). AftersevenmonthstherapywithEGFR inhibitor + immunmodulatorypreparations

  47. MEK + BRAF Inhibitors • MEK (MitogenactivatedExtracellularsignal regulationKinase) – inhibitorscan down regulate a receptor tyrosinkinasemediatedsignaling pathway (byinhibition of mitogenactivated protein kinase /MAPK/ cascade). Itcanresult in a decrease of cellproliferation. BRAF inhibitors show a synergisticeffectwith MEK inhibitors. • MEK and BRAF inhibitorshavebeenidentifiedastherapeutictargets in cancer. The clinicalresultsareoftenonlytransient and completeremission is rarelyobserved. (Smith MP, Wellbrock C. ClinCancer Res • 2016 Oct 19.)

  48. . A now 59 years old patientwithinoperable (BRAF-mutant) bilaryductcancer (lowdifferentiatedadenocarcinoma) showed after 30GY radiotherapy and twocycleschemotherapy a progression and in june2016 lung, liver and brainmetastaseswereestablished in CT and MR. BRAF (p.V600E) 15% clinicalrelevant driver mutation TP53 (p.Q16fs*28) 22% clinicalrelevant driver mutation From 04.07.2016: BRAF+MEK inhibition dabrafenib (2x150 mg per os ) + trametinib (1 x 2 mg per os) Parallel 3 g BIOBRAN / DIE

  49. PET-CT investgations of lungmetastasis. Effect of treatment MEK + BRAF inhibitorscombinedwith BIOBRAN (3 gramdaily). Prior totreatmentThreemonthslater

  50. MR investgations of Brainmetastasis. Effect of treatment MEK + BRAF inhibitorscombinedwith BIOBRAN (3 gramdaily).BeforetherapyEightmonthslater

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