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No conflicts of interest PAMP-Immuntherapie (C) Uwe Hobohm 1
2011: Eight hallmarks of cancer
• unbegrenztes Teilungspotential
• Neurekrutierung einer unabhängigen Blutversorgung
• Stillegung der Apoptose
• das Ablegen der Abhängigkeit von externen Wachstumsfaktoren
• die Insensitivität gegen wachstumsbremsende Signale aus dem
umliegenden Gewebe
• Gewebeinvasion und Metastasierung
• Reprogrammierung des Energiemetabolismus’
• Umgehung der Abwehr des Immunsystems
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
PAMP-Immuntherapie (C) Uwe Hobohm 2
The hypothesis of Darwinian evolution of cancer: accumulation
of rare mutations
PAMP-Immuntherapie (C) Uwe Hobohm 3
„Most human cancers develop over decades of time“ (Weinberg)
Proctor Nat.Rev.Canc. 1(2001)82
PAMP-Immuntherapie (C) Uwe Hobohm 4
Multistep
tumorigenesis
over decades
PAMP-Immuntherapie (C) Uwe Hobohm 5
What most General
people believe situation:
but is rare (e.g. polyclonality of
AML) malignant
tissue
PAMP-Immuntherapie (C) Uwe Hobohm 6
Von einem Tumor wurden
188 Biopsien genommen
und sequenziert. Es fanden
sich 70000 Mutationen,
keine Biopsie war gleich.
Marusyk Nat.Rev.Canc 12(2012) 323
PAMP-Immuntherapie (C) Uwe Hobohm 7
150 prostate cancer biopsy samples : on average 28000 genetic aberrations per sample
• 150 samples of metastatic
castration resistant prostate cancer
(mCRPC) (X-axis)
• on average 4.4 genetic defects
(see yellow box) / MB, -> 28000
per diploid genome
• samples may not show a single
mutation in any oncogene (red
bar) !
Figure 2. Integrative Landscape Analysis of Somatic and Germline Aberrations in Metastatic CRPC Obtained through DNA and RNA
Sequencing of Clinically Obtained Biopsies
(C) Uwe Hobohm PAMP and cancer
Columns represent individual affected individuals, and rows represent specific genes grouped in pathways. Mutations per Mb are shown in the upper histogram, and
incidence of aberrations in the cohort is in the right histogram. Copy number variations (CNVs) common to mCRPC are shown in in the lower matrix, with pink
representing gain and light blue representing loss. Color legend of the aberrations represented including amplification, two copy loss, one copy loss, copy neutral
loss of heterozygosity (LOH), splice site mutation, frameshift mutation, missense mutation, in-frame indel, and gene fusion. Cases with more aberration in a
gene are represented by split colors.
Gezielte Therapien sind längst nicht so erfolgreich wie viele annehmen
Targeted therapies tend to be least successful in patients who have exhausted all
standard treatments, like Ms. DiCanto. In a study published last year in Cancer
Discovery, precision medicine failed to help 93 percent of 1,000 patients.
At the most recent meeting of the American Society of Clinical Oncology, researchers
presented four precision-medicine studies. Two were total failures. The others weren’t
much better, failing to shrink tumors 92 percent and 95 percent of the time.
The studies received almost no news coverage.
NYT 12.9.2018
https://www.nytimes.com/2018/09/11/opinion/cancer-genetic-testing-precision-medicine.html
PAMP-Immuntherapie (C) Uwe Hobohm 9
Krebszellen sind nicht unsichtbar für das
Immunsystem
PAMP-Immuntherapie (C) Uwe Hobohm 10Correlation between TIL and prognosis • MacCarty WC, Mahle AE. Relation of differentiation and lymphocytic infiltration to postoperative longevity in gastric carcinoma. J Lab Clin Med 6, 1921, 473-480 • Correlation between number of TIL and survival rate (Black et al, Surg.Gynecol.Obstetr 102 , 1956, 599-603) •Aaltomaa S, Lipponen P, Eskelinen M, et al: Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 28A:859-864, 1992 • High numbers of antigen-experienced tumor-specific cytolytic T-lymphocytes in metastatic lymph nodes (Romero et al., J.Exp.Med. 188, 1998, 1641-1650) • Mccoy, J. L., Rucker, R., and Petros, J. A. Cell-mediated immunity to tumor-associated antigens is a better predictor of survival in early stage breast cancer than stage, grade, or lymph node status. Breast Cancer Res., 60: 227–234, 2000. • 6-Year survival rate in ovary cancer patients: 50% with TIL, 0% w/o TIL (NEJM 348, 2003, 203) • 6-Year survival rate in breast cancer patients: 60% with TIL, 0% w/o TIL (Immunity 92(3), 2004, 137-48) •Quantity and quality of immunes responses is remarkable reliable prognostic indicator. Strong in situ immune reaction in tumors correlated with favourable prognosis (hazard ration 2.4 p
...however, there is time coincidence with feverish infection
1918 collection of 302 cases, 44 complete remissions, 27/302 infections (small pox,
malaria, pneumonia, tuberculosis), 69 "incomplete operation often
accompanied by post-operative fever" (9-28%) (Rohdenburg J.Canc.Res. 3,
193-225)
1951 In a cohort of 300 cases of childhood leucemia, 26 spontaneous remissions
were observed. 21/26 (80%) were accompanied by infection (Diamond and
Luby, Am.J.Med. 10, 238ff)
1971 Review on 224 cases, in 62 cases (28%) either an infection or a persistent
temperature elevation was observed prior to regression (Stephenson et al,
Surg.Gynecol.Obstetr. 133, 649-655)
1990 Review on 741 cases, infection and 'operative trauma' were reported in 4%
cases (30, should be at least 62 ! since Stephenson’s cases were included and
re-reviewed=>lack of awareness) (Challis and Stam, Acta Oncol. 29, 545-550)
1998 68 well documented melanoma cases, preceded in 21 (31%) cases by a febrile
infection (most erysipelas again) (Maurer und Kölmel, Onkologie 21, 14-18)
2001 Hobohm Canc.Immunol.Immunother. 2001;50(8):391-6.
PAMP-Immuntherapie (C) Uwe Hobohm 12Anti-correlation between infection and cancer was observed on many occasions
(find complete table under www.pamp-therapie.de/referenzen)
therapeutic /
Observation Year pathogen reference
prophylactic
Deidier: Dissertation Medecinal et
Lower risk of cancer in syphilitic prostitutes prophylactic 1725 Treponema pallidum Chirurgical sur les Tumeurs, Paris
Mycobacterium
Low risk of cancer in tuberculosis patients prophylactic 1929 tuberculosis Am J Hyg 9, 97
Lower risk of cancer in malaria patients prophylactic 1929 Plasmodium falc., Z. Krebsforsch. 29: 330-33
malariae, vivax (1929)
Z. Krebsforsch. 29: 468-90
Occasional remissions in HL after measles therapeutic 1971 Morbillivirus Lancet. 1971 Mar 20;1(7699):
attack 593
Patients developing empyema after lung cancer surgery
have improved 5-year survival (50% (n=18) vs 22%
therapeutic 1972 diverse NEJM 287, 1013
(n=411))
Lower cancer incidence after Herpes infections prophylactic 1987 Herpes simplex J Chron Dis 40, 967
Post-transfusional hepatitis in patients with 1982, NEJM 307, 1712
acute myelogeneous leukemia doubles survival therapeutic 1992 Hepatitis viruses Leukemia 6, 1036
rate
A history of common colds or gastroenteric influenza
was found to be associated with a decreased cancer common cold J Canc Res Clin Oncol
risk (odds ratio 0.18 and 0.23 vs. population and prophylactic 1991
viruses 117, 339
hospital controls, resp.)
68 well documented cases of spontaneous Streptococcus
regression from melanoma, preceded in 21 therapeutic 1998 pyogenes Onkologie 21, 14
(31%) cases by a febrile infection (9/21 cases)
Inverse correlation between melanoma risk and number of
recorded infections on one hand and between melanoma risk
and fever height on the other hand, leading to a combined prophylactic 1999 diverse Melanoma Res 9,511
reduction of melanoma risk of about 40% for people with a
history of three or more infections with high fever above
38.5oC
More than two-fold higher incidence of cancer in Europe, GUS World Health Organization,
and US compared to Africa and Asia of 381 vs 156 (ten most
prominent cancer forms, age standardized rate per 100000 prophylactic 2003 diverse
population; in Africa and Asia a significant higher rate of infections IARC Press;
is assumed here
Prior immunisation of melanoma patients with vaccinia or Eur J Cancer 41(1):
BCG is associated with better survival (age matched prophylactic 2005 BCG, vaccinia
controls) 118--25
PAMP-Immuntherapie (C) Uwe Hobohm 13Vaccination using bacterial
extracts Spontaneous regression cases
• Coley’s therapy undoubtedly led to numerous • A large fraction (30%-80%) of spontaneous regressions
amazing cures (but failed in other cases) which can be correlated with a hefty feverish infection
have not been explained until today • Diseases involved include tuberculosis, malaria,
(Hobohm, Brit.J.Canc. 2005) pneumonia, abscess, with an abundance of erysipelas
(Hobohm Canc.Imm.Immunoth. 2001)
PAMP
(Hobohm, Grange, Stanford
Crit.Rev.Imm. 2008) Tumor immunology
• In many if not all cases tumor-specific T-cells can
be found in or around tumor tissue
• These T-cells usually are not activated, likely because
co-stimulatory signals are missing
• Fever / external heat generates a higher rate of
tumor/normal cell debris, i.e. likely delivers
Epidemiology more tumor antigens
• A personal history of three or more feverish infections reduces the
likelihood to develop melanoma later by 40%
• Post-operative infections correlate with improved lung cancer
survival
(Maletzki, Hobohm et al. Canc.Imm.Immunoth. 2013)
References: www.pamp-therapie.de
PAMP-Immuntherapie (C) Uwe Hobohm 14T-cells are activated by DC, DC are activated by antigen and PAMP
PAMP
PAMP-Immuntherapie (C) Uwe Hobohm 15Cancer mouse treatment with single and multiple PAMP
1600
Kontrolle Kontrolle
Flagellin (25µg/kg KG)
P1
Maletzki C, Linnebacher M, Savai R, Hobohm U.
1400 LPS (2mg/kg KG) P2
Cancer Immunol Immunother. 2013;62(8):1283-1292.
MDP (100 µg/kg KG)P3
Resiquimod (60µg/kg P4KG)
1200
P2+P3+P4MDP)
Kombi (LPS, Resiquimod,
1000
800
600
400
200
0
Tag 0 Tag 4 Tag 7 Tag 11 Tag 14 Tag 17 Tag 21 Tag 24
C57BL/6J-Mäusen (5 pro Gruppe) wurden Panc02 Bauchspeicheldrüsentumorzellen am Tag minus 8 verabreicht. Die PAMP-
Behandlung erfolgte nach Auswachsen sichtbarer Tumoren (ca. 50mm³). Insgesamt wurden 10x lokale Injektionen im Abstand
von 2-3 Tagen an den Tagen 0-21 durchgeführt. Die Mäuse der Kombigruppe (3 PAMP Substanzen gemeinsam) zeigten nahezu
kein Tumorwachstum, bei 4/5 verschwand der zunächst sichtbare Tumor innerhalb von 21 Tagen (zusammen mit
M.Linnebacher, Univ. Rostock)
PAMP-Immuntherapie (C) Uwe Hobohm 16Cancer mouse treatment with single and multiple PAMP
1 PAMP 3x/Woche (insges.10x): keine Heilung 2 PAMP 2x/Woche (insges.6x): keine Heilung
3 PAMP 3x/Woche (insges.10x): Heilung
1600
Kontrolle
Flagellin (25µg/kg KG)
1400 LPS (2mg/kg KG)
MDP (100 µg/kg KG)
Resiquimod (60µg/kg KG)
1200
Kombi (LPS, Resiquimod, MDP)
1000
800
600
400
200
0
Tag 0 Tag 4 Tag 7 Tag 11 Tag 14 Tag 17 Tag 21 Tag 24
(Maletzki C, Linnebacher M, Savai R, Hobohm U. (Stier, Linnebacher et al. Clinic. Dev. Immunol
Cancer Immunol Immunother. 2013;62(8):1283-1292.) 2013)
PAMP-Immuntherapie (C) Uwe Hobohm 17Breaking tolerance by PAMP
There are indications that the application of PRRL can help to break tolerance. The
therapeutic application of CpG in tumour bearing mice decreases MDSC and blocks
suppressive activity on T-cell proliferation (Zoglmeier, C. et al. Clin Cancer Res 17,
1765-1775; 2011). We confirmed a similar decrease on MDSC count after PRRL-
application, likely leading to a similar lift of T-cell suppression. (together with
M.Linnebacher, Univ.Rostock)
PAMP-Immuntherapie (C) Uwe Hobohm 18In this retrospective phase-1 study we report on the fever induction capacity and
safety of applications of bacterial extracts, combinations of bacterial extracts with
approved drugs, and combinations of approved drugs in 131 mainly cancer patients.
Adverse reactions were those which can be expected during a feverish infection
and mild. Over 523 fever inductions, no severe adverse reaction was observed.
PAMP-Immuntherapie (C) Uwe Hobohm 19PAMP-Immuntherapie (C) Uwe Hobohm 20
PAMP-Immuntherapie (C) Uwe Hobohm 21
PAMP-Immuntherapie (C) Uwe Hobohm 22
PAMP-Immuntherapie (C) Uwe Hobohm 23
PAMP-Immuntherapie Behandlungsprotokoll für Ärzte
http://www.pamp-therapie.de/referenzen/PAMP-protokoll-aerzte.pdf
PAMP-Immuntherapie (C) Uwe Hobohm 24PAMP-Immuntherapie (C) Uwe Hobohm 25
PAMP-Immuntherapie (C) Uwe Hobohm 26
Idealerweise wird die PAMP-Anwendung dreimal pro Woche, beispielsweise Montag
Mittwoch, Freitag, durchgeführt. Üblicherweise erfolgt die Infusion nüchtern am Morgen
über 30-120 Minuten.
PAMP-Immuntherapie (C) Uwe Hobohm 27Haupthindernisse in den Köpfen Die Abwesenheit von Fieber korreliert mit einem besseren Gesundheitszustand als die Anwesenheit (Fieber = Gefahr) Eine billige, nebenwirkungsarme Krebstherapie kann nicht funktionieren Wenn eine einfache Krebstherapie wirken würde, hätte man sie längst identifiziert PAMP-Immuntherapie (C) Uwe Hobohm 28
Haupthindernisse in Kliniken Leitlinien off-label erfordert stationäre Unterbringung Abweichung vom durchstrukturierten Klinikalltag Innovationsscheu bei den Entscheidern in der Klinik Abrechnung (fehlende Kassenziffern) Unsicherheit beim Umgang mit Pseudo-Progress PAMP-Immuntherapie (C) Uwe Hobohm 29
Haupthindernisse in Privatkliniken und Privatpraxen Haftpflichtversicherung Abrechnung (fehlende Kassenziffern) Bereitstellung eines Raumes mit Kreislaufüberwachung und regelmässiger Kontrolle durch eine Fachkraft PAMP-Immuntherapie (C) Uwe Hobohm 30
Vielen Dank für Ihre
Aufmerksamkeit
www.pamp-therapie.de
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