Prof. T. Hajtó: Medical University Pécs /Hungary

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

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

• Containing PAMP like Arabinoxylan molecules is BioBran the best standardized immunomodulator which can be used in the tumour therapy?

Tumour-associated

• Tumour-associated

• Ag-s together

• with other self

• proteins are regu-

• larly broken down

• in proteosome

• producing two million

• peptids pro second.

• They are presented

• for CD8-T lymphocytes

• by MHC-I Ag-s which

• are regularly produced

• in endoplasmic reticu-

• lum (with 150 000/sec

• velocity) but only

• 150/sec can get to the cell surface.

Twenty years ago

• 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.

New clinical efforts to inhibit the negative co-stimulatory signals (such as PD1-PDL-1 and 2 as well as CD80/CD86 and CTLA-4) to improve T cell activation /Neg. signals /-----------positive co-stimulatory signals--------------/

• New clinical efforts to inhibit the negative co-stimulatory signals (such as PD1-PDL-1 and 2 as well as CD80/CD86 and CTLA-4) to improve T cell activation /Neg. signals /-----------positive co-stimulatory signals--------------/

• Nivolumab –Opdivo

• There is a significant

• clinical benefit in

• melanoma and cancer

• of kidney

• PROBLEM:

• Quantitative loss

• + qualitative change

• of MHC-I

• INNATE IMMUNE SYSTEM

• Consequently, again and again growing attention is focusing on the effector cells of innate immune system which are able to kill tumor

• cells in non-MHC restricted 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

Suggested effect of lectin (ML)

• Suggested effect of lectin (ML)

• and Arabinoxylan

.

• .

• After 30 min incubation of FITC labelled lectin

• molecules in whole blood

Suggested effect of lectin (ML)

• Suggested effect of lectin (ML)

• and Arabinoxylan

NaCl

• NaCl
• LECTIN ARABINOXYLAN

.

• .

• Mo Tue We Thu Fri Sat Sun
• __________________________________________________________
• Lectin
• in ME: 0.5-1 ng/Kg - - 0.5-1 ng/kg - - -
• s.c. s.c.
• ________________________________________________________
• Arabino- 12-45 - - 12-45 - - -
• xylan in mg/kg mg/kg
• BioBran p.o. p.o.
• ________________________________________________________
• Ghoneum M.: Int. J. Immunotherapy
• 14(2): 89-99, 1998
• FIRST CONTROLLED
• CLINICAL TRIAL 2010

• In spite of fact that Arabinoxylan (in BioBran) exhibits a clinical evidence, the „door of castle” is not opened. No further clinical trials were carried out. The reason is simple: in spite of many research a well standardized and evidence based phytotherapy is ignored by the „GENERAL’ of castle” since it is phytotherapy.

• In Switzerland we have an application submitted to an ethical comission to get a permission for a cohort clinical trial with standardized plant immunomodulators. It was refused. Only case reports were permitted. Therefore in this lecture several interesting case reports will be presented.

.

• .

• Primary tumor Other therapy Imm.Th. Observation Clinical progress

• Breastcancer Hormone (Femara) L+B 12 mo CR

• BreastCancer Xeloda1500mg/d. L+B 11 mo nearly CR
• Coloncancer Avastin +FOLFIRI L+B 4 mo CR
• ColonCancer Op+FOLFIRI-FOLFOX L+B 31 mo CR
• Hajto T, Kirsch A. J. Cancer Res Updates 2013; 2: 1-9
• Next pictures presents the second patients, who in spite of intensive chemotherapy and surgical operation had a very rapid progression..

• After treatment for three months

• After treatment for seven months

• Hajto T, Kirsch A: J Cancer Res Update 2013; 2:1-9

• Because of tumour-induced suppression of type-1 natural immunity

• TODAY

• We know that the dec-

• rease of type-1 system TU-induced dominance of type-2

• reduces the expression of cells producing Growth Factors

• KAR-receptor (NKG2D) can decrease the expression of NK ligands.

• Oncological treatments in general show no beneficial effect.

• THERE IS AN EXCEPTION: GEMCITABIN

• Gemcitabine (Gemzar) can induce

• an enhanced expression of NKGD2

• After Gemcitabine treatment
• expression of MICA, MICB and
• ULBPs (stress related peptids) upregulated
• Result: increase in NK activity
• increase in NK sensitivity of TU cells

3. Has a combination of plant immunomodulator-induced activation of type-1 cells with also NK stimulating GEMCITABINE a clinical benefit ?

• 3. Has a combination of plant immunomodulator-induced activation of type-1 cells with also NK stimulating GEMCITABINE a clinical benefit ?

Prior to the therapy After six months

• Prior to the therapy After six months

• the attending physician in the Oncology Department was not ready to continue it.

.

• .

• Increased expression Improvement of Growth Factor by LECTIN and induced low expression of

• ARABINOXYLAN NK-ligands (stress-related

• molecules) by GFR inhibitors

• Four months later after

• chemoterapy (4 cycles 300mg

• Carboplatin and 200mg Taxol).

• After seven months therapy with EGFR inhibitor + immunmodulatory preparations

• MEK (Mitogen activated Extracellular signal

• regulation Kinase) – inhibitors can down regulate

• a receptor tyrosin kinase mediated signaling

• pathway (by inhibition of mitogen activated

• protein kinase /MAPK/ cascade). It can result in

• a decrease of cell proliferation. BRAF inhibitors show

• a synergistic effect with MEK inhibitors.

• MEK and BRAF inhibitors have been identified as therapeutic targets in cancer. The clinical results are often only transient and complete remission is rarely observed. (Smith MP, Wellbrock C. Clin Cancer Res

• 2016 Oct 19.)

• A now 59 years old patient with inoperable (BRAF-mutant)

• bilary duct cancer (low differentiatedadenocarcinoma) showed

• after 30GY radiotherapy and two cycles chemotherapy a progression and in june 2016 lung, liver and brain metastases were established in CT and MR.

• BRAF (p.V600E) 15% clinical relevant driver mutation

• TP53 (p.Q16fs*28) 22% clinical relevant 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

• 5.) Can the regulation of nuroendocrine and the natural immune system connected with each other more closely than until now we have believed it?

• .

Frequency of NK cells among

• Frequency of NK cells among

• peripheral lymphocytes (%)

• After selective destroying

• the beta cells in Langerhans

• islets 3.1 fold increase in the

• peripheral NK level was

• observed indicating the role

• of insulin in the regulaion

• of type-1 cells.

• P<0.001 control treated group

• X +/-SEM: 23.7% +/-2.96 75%+/-2.8

• These results in animal model may be in a realationship with the following case report?

• In the right breast of an 75 years old patient a carcinoma was established by histological investigation. At the same time multiplex lung metastases were found in CT. Because of cardial problems a chemotherapy and a surgical operation were not possible.

• She reduced the doses antidiabetic drugs which were applied since a long time. Parallel standardized plant immunomodulators were given.

• After six and after 16 months complete remission of lung metastases was by CT established. Can Insulin as growth factor collaborate with the Type-2 cells?

• ? using receptor tyrosin- kinase

• mediated

• signaling

• pathway by pro-

• duction of

• EGF and other GF

• or Insulin

• can activate

• type-2 cells.

• Expression of KAR (NKG2D) decreased

• by blockade beta-adrenerg signalling

• or chemical sympathectomy We must learn to manipulate! ,

• 6.) Can the plant PAMP molecules-induced improvement in the balance of innate immune system lead to a better quality of life?

• In spite of fact that Arabinoxylan (in BioBran) exhibits a clinical evidence, the „door of castle” is not opened. No further clinical trials were carried out. The reason is simple: in spite of many research a well standardized and evidence based phytotherapy is ignored by the „GENERALS of ONCOLOGICAL castles” since it is phytotherapy.

• An other problem: Further clinical trials are very expensive, only multinational companies are able to pay for them.

-Taking these results into consideration we must

• -Taking these results into consideration we must

• learn to manipulate the regulatory axis of natural immune balance together with neuroendocrine system which can open new perspectives in the tumor therapy.

• -It also clear that these manupulations are not able to cure of malignant tumours in many cases but they can help to prolong the stagnation and remissions of the disease without side effects with improvement of QoL.

• -However, there is a great problem: PAMP molecules (which are able to activate type-1 cells and inhibit the Growth Factor producing type-2 cells) occur only in the nature (in bacteria or in plants). Chemistry is not able to manufacture these appropriate PAMP configurations. In spite of clinical

• evidence standardized plant extracts banished from the medical world. „The door of castle is closed!” What must we do?

- If the standardized plant immunomodulators will be ignored such as food supplements and not as drugs in the future too, it means serious difficulties for the further tumor research.

• - If the standardized plant immunomodulators will be ignored such as food supplements and not as drugs in the future too, it means serious difficulties for the further tumor research.
• Middle-Europa must keep together to protect the evidence based phytho- research.
• - What can we do?

My answer originates with a slight modification from the world-famous novel of Leo Tolstoy: War and Peace.

• My answer originates with a slight modification from the world-famous novel of Leo Tolstoy: War and Peace.

• Pierre Bezukhov: „I only wished to say that ideas that have great results are always simple ones. The whole of my idea is that if people in „castle” are united and constitute a power, then „researchers outside” must do the same. Now that’s simple enough.”

T.R. Allen S. Könermann Perjési Pál

• T.R. Allen S. Könermann Perjési Pál

• Aponyi Ildikó Kovács Éva C. Rordorf

• Balogh Péter Kuzma Monika R. Saller

• Baranyai Lilla C. Lanzrein A. Savoie

• Berki Timea V. Lavastre B. Sütterlin

• Boldizsár Ferenc H. Lentzen G. Spagnoli

• Fischer János  H. Lösert T. Schwarz

• Fodor Krisztina U. Mengs F. Steinberg

• M. Fornalski Nagy G. K. Vehmeyer

• H-J. Gabius Németh Péter K. Weber

• D. Girard Pallai Zsolt R. Weyhenmeyer

• R. Herrmann Pálinkás László B. Wörmann

• K. Hostanska Papp Szidónia H. Zinke

• Horváth Anna M. Pelletier

• A. Kirsch

• 17 Institute (16 Europa, 1 Kanada)

BIOBRAN/IMMUNOBRAN RESEARCH

• BIOBRAN/IMMUNOBRAN RESEARCH

• By Daiwa Pharmaceutical Company developed and by the Immunologist Dr. Ghoneum in the Medical University in Los Angeles thoroughly investigated.

• Other important participants in the BioBran-Research

• from six different countries:

• Tomidato Miura Yuso Endo Hirosi Kanbayashi

• Sastry Gollapudi Ikou Ohara Ritsuko Tabuchi

• Kumiko Ottai Dana Cholujova Jana Jakubikova

• Ján Sedlak Nariman K Badr El-Din Eman Noaman

• Motohiro Matsuura Sudhanshu Agrawal Surina Zheng

• Hiroo Sanada Shizuka Hirai Yukari Egashira

• Hirofumi Dohi Kihachiro Takahara Kamataro Sano

• Jimmy Brown Kazutoshi Kaketani Tomoroni Kawai

• Mai Hong Bang Tan Van Riep Jozef Duraj

• Antonio Pérez-Martínéz Matthias Manuel Pfeiffer Jaime Valentín

• LD50