Prof.Dr. Uwe Hobohm, University of Applied Sciences,
35390 Giessen, GermanyCV Uwe Hobohm
PhD Biology University Bremen, cell biology 1989
EMBL-Heidelberg, bioinformatics department 1990-1994
DFG-Habilitation grant, Univ.Bremen 1995-1996
F.Hoffmann-La Roche Basel, bioinformatics 1996-2002
Univ.Appl.Sc.Giessen, bioinformatics from 2002
Abstract
Cumulative evidence from different research frontiers - historical experiments using bacterial extracts in cancer patients, case studies on spontaneous regression, infection epidemiology, cancer immunology - when wired together, indicate that the role of the human immune system, in particular the so-called innate part of the immune system, in the prevention and reversal of cancer has been underestimated. This has implications both for the prophylaxis and therapy of cancer.
PAMP-molecule
Introduction
Spontaneous regressions and remissions from cancer are still regarded as a mystery. But a careful analysis of case studies reveals that many, if not a majority, of cases have a close connection in time with a hefty feverish infection. This observation, which was published 2001, can be well aligned with early cancer treatments by Busch, Coley and co-workers more than 100 years ago, and with epidemiological data collected and discussed recently (2005 , 2008a , 2008b).
Meanwhile, a biochemical explanation for all these links is available. Pathogenic substances collectively termed 'pathogen associated molecular pattern' (PAMP) or 'Toll-ligands' most likely are responsible. These substances act on the innate immune system and enable an enhanced immune reaction compared to antigen alone.
While the focus in cancer immunotherapy has been on antigen alone, i.e. the adaptive immune system, attention is shifting very recently towards the involvement of the innate system. Several PAMP are presently in diverse clinical trials. However, the way these drugs are applied in cancer immunotherapy might need revision (see Hobohm, Grange, Stanford "PAMP in cancer immunotherapy", Critical Reviews in Immunology 28(2):95–107)
Der menschliche Körper wird von Laien wie Fachleuten als Maschine betrachtet, die zu schwach ist, mit Krebs fertigzu-werden. Doch das ist falsch. Auch bei Krebserkrankungen können sogenannte Spontanregressionen auftreten, die bis-weilen in eine Heilung münden, sogar in weit fortgeschrittenen Fällen. In der medizinischen Fachliteratur findet man hunderte Berichte über Spontan-regressionen, zusätzlich muss man von einer erheblichen Dunkelziffer ausgehen. Im Prinzip kann das menschliche Immun-system also Krebs besiegen. Spontanregressionen konnten bislang nicht erklärt werden. Es zeigt sich jedoch, dass viele, wenn nicht die meisten Spon-tanregressionen nach einem heftigen fiebrigen Infekt auftraten. Darüberhinaus gibt es zahlreiche Studien, die zeigen, dass eine persönliche Historie von Infekten das Risiko, Krebs zu bekommen, deutlich senkt. In diesem Essay soll beleuchtet werden, ob und wie bakterielle und virale Infekte und Stoffwechselprodukte zur Behand-lung von Krebs genutzt werden könnten. Heinz-Uwe Hobohm ist Biologe und Professor für Bioinformatik
Prof.Dr.Uwe Hobohm, Bioinformatics, University of Applied Sciences Giessen
Hobohm,U. and Sander,C. (1993): "Does the HIV NEF protein mimic the MHC ?",
FEBS Letters 333/3, 211-213 (impact factor 3.3)
Hobohm,U. and Sander,C. (1993): "Enlarged representative set of protein structures" ,
Protein Science 3, 522-524 (impact factor 3.1)
Hobohm,U. and Meyerhans,A. (1993): "A pattern search method for putative anchor
residues in T cell epitopes", Europ.J.Immunol. 23, 1271-1276 (impact factor 4.7)
Hobohm,U., Scharf,M., Schneider,R. and Sander,C. (1992): "Selection of
representative protein data sets", Protein Science 1, 409-417 (impact factor 3.1)
Hobohm,U., Hildebrandt,A. and Rensing,L. (1990): "A purified cellular extract
accelerates the cell cycle in Physarum polycephalum", Exp.Cell Res. 191, 332-336 (impact
factor 3.7)
Hobohm,U., Cornelius,G., Taylor,W. and Rensing,L. (1984) : "Is the circadian clock of
Gonyaulax held stationary after a strong pulse of anisomycin ?", Comp. Biochem.
Physiol 79A/3, 371-378
(impact factors from 2007)
Papers (not peer reviewed)
Hobohm, U.: „Stimulating innate immunity as cancer therapy“, MacGrawHill Yearbook
of Science and Technology 2010 (invited review)
Hobohm, U: „Healing Heat: Harnessing Infection to Fight Cancer“. American
Scientist 97 (2009), 34-41
Hobohm, U: JMM Past and Present, commentary in Journal of Molecular Medicine,
February 2002
Hobohm,U. (1996): "Scottish randomized controlled trial of conservation for breast
cancer", letter to Lancet 348, 1458
Books
Hobohm, H.-U.: "Healing Heat", ISBN 9783837037463, BoD 2009, 88 pages
Hobohm, H.-U.: "Heilende Hitze - ein Essay zur Immunabwehr des Krebses", ISBN
9783837014174, BoD 2008, 88 pages
Hobohm,H.-U.: "Wegweiser zur Krebsheilung", Hugendubel, München, March 2001,
235 pages
Hobohm,H.-U.: "Selbsthilfe bei Krebs", Haug-Hüthig, Heidelberg, 1998, 205 pagesProf.Dr.Uwe Hobohm, Bioinformatics, University of Applied Sciences Giessen
Peer reviewed papers
Griep,S, Hobohm,U: „PDBselect 1992-2009 and PDBfilter-select“, Nucleic Acids
Research , January 2010 (impact factor 6.9)
Hobohm,U: „Toward general prophylactic cancer vaccination“, BioEssays 31 (2009),
1071-1079 (impact factor 5.4)
Hobohm U, Grange J, Stanford J: "Pathogen associated molecular pattern in cancer
immunotherapy", Critical Reviews Immunology, 2008, 28(2):95-107 (impact factor
4.1)
Hobohm U: "Fever therapy revisited", British Journal of Cancer 92 (2005), 421-425
(impact factor 4.6)
Engel T, Lueken A, Bode G, Hobohm U, Lorkowski S, Schlueter B, Rust S, Cullen P,
Pech M, Assmann G, Seedorf U.: "ADP-ribosylation factor (ARF)-like 7 (ARL7) is
induced by cholesterol loading and participates in apolipoprotein AI-dependent
cholesterol export.", FEBS Lett. 2004 May 21;566(1-3):241-6 (impact factor 3.2)
Faller,D., Voss,H., Timmer,J. and Hobohm,U.: "Normalization of DNA microarray
data by non-linear correlation-maximization", Journal of Computational Biology, 10
(2003) 751-762
Hobohm,U.: "Fever and cancer in perspective", Cancer Immunology Immunotherapy,
50 (2001) 391-396 (impact factor 3.2)
Gosslau,A., Ruoff,P., Mohsenzadeh,S., Hobohm,U. and Rensing,L.: "Heat shock and
oxidative stress-induced exposure of hydrophobic protein domains as common signal in
the induction of hsp68", Journal of Biological Chemistry 276 (2001), 1814-1821
(impact factor 5.6)
Hobohm,U., Berndt,P. and Langen,H.: "Reliable automatic protein identification from
matrix assisted laser desorption/ionization mass spectrometric peptide fingerprints",
Electrophoresis 20 (1999), 3521-3526 (impact factor 3.6)
Schneider,G., Schuchhart,J., Hobohm,U., Jagla,B. and Wrede,P. (1996):
"Classification of local protein backbone motifs by KOHONEN networks", Minimal
Invasive Medizin 7,164-168
Hobohm,U. and Sander,C. (1995): "A sequence property approach to searching protein
databases", J.Mol.Biol, 251, 390-399 (impact factor 4.5)
Burkhardt,E., Adham,I.M., Hobohm,U., Murphy,D., Sander,C. and Engel,W. (1994):
"A human cDNA coding for Leydig insulin-like hormone (Ley I-L)", Molecular
Endocrinology 94, 91-94 (impact factor 5.4)
Hobohm,U., Houthaeve,T. and Sander,C. (1994): "Amino Acid analysis and protein
database compositional search as a rapid and inexpensive method to identify proteins",
Analytical Biochemistry 222, 202-209 (impact factor 3.0)Prof.Dr.Uwe Hobohm, Bioinformatics, University of Applied Sciences Giessen Citation Index October 2009: 1730
Definitions
Tumor regression
Shrinkage or disappearance of a palpable neoplasm, temporary or long lasting
Tumor remission
Improvement of a neoplasm of hematopoetic origin, temporary or long lasting
PAMP
“Pattern associated molecular pattern”, also called Toll-ligands; substances from pathogens (bacteria, viruses, fungi, worms) not found in pathogen hosts, which act as danger signals for the innate immune system and can activate dendritic cells to complement a full blown immune response.
Innate immune system
Evolutionary older part of the immune system acting fast but unspecific against pathogen invasion, can provide signals necessary for a full blown reaction of the adaptive immune system.
Adaptive immune system
Part of the immune system allowing adaptive responses like antibodies and specific T-cells, provides immunologic memory.
Th1 / Th2 - immune response
Adaptive immune responses require involvement of so-called T-helper lymphocytes. These were originally divided into two subsets. Th1 cells activate macrophages and CD8-cells (cellular immunity) while Th2 cells activate B-cells for antibody production (humoral immunity). This coarse classification is under refinement involving other subtypes like Th9, Th17 and Treg.
FAQ
What is the main message the study of spontaneous regressions can provide ?
The curative power of the human body with respect to cancer has been underestimated. This should have consequences for the therapy, but even more in prophylaxis.
How frequent are spontaneous regressions and remissions ?
Until recently, it was believed that these are rare events. It has been estimated that they occur with a frequency of 1/10000 - 1/1 Mio cancer cases with bias for particular forms of cancer like melanoma, sarcoma, neuroblastoma. A majority of these regressions is temporarily. How large the fraction of curative events is, is difficult to estimate, since patients often are “lost on follow-up”, i.e. do not show up in the clinic again. In 2001 we could show that many, if not a majority of spontaneous regressions were preceded by a feverish infection. Our 2001-hypothesis that an unspecific activation of the innate immune system is at the core of spontaneous regressions has gained evidence since.
A new study indicates that the rate of spontaneous regression has been underestimated ?
In a recent publication (Arch.Intern.Med 168,21; Nov.24 2008; www.archinternmed.com) it has been shown that spontaneous regressions can be very frequent: they happen in up to 20% of breast cancer cases. How many of those regression happened after an infection was not investigated in this study. If this result becomes confirmed, the self-healing capacity of the human body has been drastically underestimated. This would have profound consequences in therapy: the gap between tumor rejection and non-rejection might be smaller than we thought, as might be the effort needed to assist the immune system.
Why has the phenomenon of spontaneous regression from cancer not been investigated thoroughly ?
Spontaneous regressions and remissions from cancer have been observed since cancer has been defined as a distinct remedy. Nevertheless, the phenomenon of spontaneous healing in cancer has never been regarded as instructive in main stream research. Several causes for this neglect can be outlined. The phenomenon is thought to be rare; its circumstances must be fathomed retrospectively; casual events without clear cut causative evidence are difficult to publish; a certain closed-eyes attitude among many clinicians, if not blunt ignorance: even in November 2005, an article in “Deutsches Ärzteblatt” states “There is still no indication how a spontaneous regression could be stimulated.”
Some literature seems to indicate a cancer inducing effect of infections ?
This correlation is certain for some viral infections, e.g. papillomavirus, and chronical infections. The majority of evidence indicates beneficial effects of short term, curated and healed proliferative infections on the risk to develop cancer.
If there is a real beneficial effect of fever, why has it not been considered so far in cancer immunotherapy ?
The body of literature showing beneficial effects of feverish infection on cancer is immense, it consists of several hundred publications. One can find many voices in the medical literature over the last 150 years back which adress these findings. But these voices have infrequently been spoken out, did not provide any or no convincing explanation, have not been heard by many and were not considered important by many. The supportive evidence these voices present has been disregarded or was interpreted as too weak. On top, for many, radiotherapy and chemotherapy deemed to be answer enough.
More than 100 years ago Busch, Coley and contemporaries infected cancer patients deliberately using bacterial extracts. How were the results ?
Coley and others achieved miraculous cures in some patients and failed in others by injecting bacterial extracts (Strep.pyogenes and Serr.marcescens mixed) multiple times. Their publications were not written according to present day standards, so crucial parameters are difficult to pinpoint. Benefit seemed to depend on i) the particular form of cancer, ii) extract preparation, iii) length of treatment, iv) site of injection, v) level of fever achieved and perhaps vi) patients individual genetic background. In an attempt to compare Coley's results, Richardson et al. (Alt.Ther.Health.Med .5 (1999) 42) tried to match 128 Coley cases with 1675 controls from the SEER cancer registry, with groups matched on age, ethnicity, stage and radiation treatment status. The median survival was 8.9 years for Coley's patients and 7.0 years for the modern group. Ralph Moss (pers.comm.) points out that Coley's results varied depending on the extract preparation. While there was no five-year survival with "Lister formula VIII and Sloan-Kettering formula XIV", 5-year survival was 58% with "Buxton formulas IV, V, VI" and 67% with "Tracy formulas X,XI". Injections close to tumor seemed to fare better than systemic injections. His daughter Helen Coley-Nauts published a paper in 1990 (Adv.Exp.Med.biol 267, 483-500) indicating that when treatment was continued for long (>= 6 month) and the best preparations are considered, 5-year survival reached an astonishing 80% in cases of inoperable soft tissue sarcoma.
How could fever therapy be implemented ?
Coley treated his patients by injecting a heat sterilized extract of Streptococcus and Serratia extracts once or twice a week. Other bacterial or viral extracts leading to stimulation of the innate immune system and to generation of a Th1-response might be applicable as well. Dosage was increased until high fever above 39C was induced. This treatment was continued for weeks and month, a treatment of great strain (modern therapies can mean great strain as well). Mediator for the induction of fever and the stimulation of the innate immune system are PAMP, i.e. substances produced by pathogens.
Which substances belong to PAMP ?
PAMP is a diverse class of molecules like LPS (lipopolysaccharide from bacterial cell walls), flagellin (a protein found in bacterial propellers), dsRNA (double stranded RNA found in viruses), CpG-DNA (DNA characteristic for bacteria), zymosan (a substance found in infectious fungi) and many others. Common to PAMP is that they are not produced by human tissues and that receptors on dendritic cells in humans are specialised in detecting PAMP rapidly.
Are spontaneous regressions triggered by PAMP ?
That is our hypothesis, which has been outlined in 2008. If that is correct, spontaneous regressions might not be really "spontaneous", after all.
Can PAMP be tested in cancer immunotherapy ?
Several PAMP are in clinical trials as adjuvants - i.e. as helpers, not main actors - at the moment, however, those therapy regimen did no respect lessons from the old experiments and from recent insights into the innate immune system appropriately. In these trials i) fever is regarded as toxic adverse event rather than treatment enhancer; ii) single PAMP are applied rather than multiple; iii) number of treatments usually is much smaller than in Coley's time; iv) most patients are immune-compromised from prior treatment. The full potential of PAMP-therapy may be missed.
Which implications for prophylaxis can epidemiological studies indicating an anti-correlation between feverish infection and the risk to develop cancer have ?
A hypothetical explanation for these effects would be that feverish infections destroy pre-cancerous cells or strengthen the immune system. In any case, we should reflect whether it is wise to vaccinate against each childhood disease, to take antibiotics with each infection, to take aspirin und antipyretics against each fever. In one study, Kölmel et al. (Melanoma Res. 9, 1999, 511) showed a reduced risk of 40 percent to develop melanoma, when people with and without a personal history of infections were compared. Consider the reduction in personal sorrow and social expense if the incidence of cancer were reduced by 40 percent.
Kidney Cancer
Wirken Bakterien plus Fieber gegen Krebs? | |
| Erhard Jakobs, Pressestelle Fachhochschule Gießen-Friedberg 22.01.2008 15:07 | |
|
Inzwischen hat man auch eine plausible biochemische Erklärung gefunden: durch bakterielle Produkte, so genannte PAMP (Pathogen Associated Molecular Pattern), findet eine Stimulation des angeborenen Immunsystems statt. Das angeborene Immunsystem war bislang ein Stiefkind in der Krebsimmunologie. Man konzentriert sich bis heute - auch in der Impfstoffforschung - vor allem auf das adaptive Immunsystem, das imstande ist, Antikörper und T-Zellen herzustellen. Jedem Impfstoff sind so genannte Adjuvantien beigefügt, von denen man lange Zeit lediglich wusste, dass sie die Immunantwort um ein Vielfaches verstärken. Erst kürzlich hat man erkannt, dass Adjuvantien in Impfstoffen auf dieselben Proteine im menschlichen Körper wirken wie PAMP-Substanzen: auf die so genannten Toll-Rezeptoren. Das sind essentielle Bestandteile des angeborenen Immunsystems, die zu einer viel stärkeren Immunantwort gegen Krebszellen führen. Fieber verstärkt diese Wirkung wahrscheinlich auf vielfältige Weise. Man weiß beispielsweise, dass Krebszellen oft hitzeempfindlicher sind als normale Körperzellen. Hobohms Hypothese von 2001 gilt inzwischen als weitgehend bestätigt.
Mit den Professoren John Grange und John Stanford aus London hat der Gießener Bioinformatiker nun einen weiteren Artikel in der angesehenen Zeitschrift "Critical Reviews in Immunology" publiziert. Darin wird die derzeitige Anwendung von PAMP in Frage gestellt. Die wenigen vorliegenden klinischen Studien zu PAMP waren bislang nicht sehr erfolgreich, nach Ansicht des Autorentrios eine Folge falscher Anwendung. Anstatt einzelne PAMP über kurze Zeiträume bei austherapierten Patienten zu testen, so die Verfasser, sollte man einen Cocktail von PAMP über längere Zeit an nicht entsprechend vorbehandelten Patienten unter Fieber anwenden. Nur dann könne das volle Potential von PAMP gefunden werden. Über Hobohms Hypothesen hat der "New Scientist" im Januar 2008 berichtet. Auch der "American Scientist" hat Interesse an einem Übersichtsartikel angemeldet - beides populärwissenschaftliche Zeitschriften mit einem Millionenpublikum.
In einem gemeinsamen Forschungsprojekt mit der Universität Gießen soll nun an Mäusen geprüft werden, ob die Verabreichung von PAMP-Substanzen unter gezielter Fiebererzeugung tatsächlich die Wirkung dieser Krebstherapie verbessern kann.
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