Fever therapy

[Rich66]

Int J Hyperthermia. 2010;26(6):565-76.
Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model.

Rowe RW, Strebel FR, Proett JM, Deng W, Chan D, He G, Siddik Z, Bull JM.

joan.m.bull@uth.tmc.edu




Source

University of Texas Medical School, Division of Oncology, Houston, Texas 77030, USA.

Abstract

PURPOSE:

Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity.
MATERIALS AND METHODS:

The effect of mild heat (40 degrees C) on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumour cell line. In vivo oxaliplatin was administered at various doses and times before, during and after fever-range thermal therapy (6 h at 40 degrees C) to rats bearing an MTLn3 mammary adenocarcinoma. Tumour growth, survival, and toxicity were measured to determine treatment outcome.

RESULTS:

Heating halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24 h before thermal therapy were completely immunologically cured, while a further 11% regressed their primary tumour but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumour efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 h before fever-range whole body thermal therapy.

CONCLUSIONS:

When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumours in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.

PMID:

20707651

[PubMed - indexed for MEDLINE]

Interview with Dr. Bull on thermotherapy:
Fever Kills Cancer -- In-Depth Doctor's Interview


http://_.ivanhoe.com/channels/p_chan...?storyid=21590


Short article: http://www.ivanhoe.com/channels/p_ch...?storyid=21587

"We are using a temperature that you would get if you had a bad case of the flu," Joan Bull, M.D., an oncologist at Memorial Hermann-Texas Medical Center in Houston, Texas, told Ivanhoe.
Two days after Castelli receives chemotherapy and immune-boosting drugs, he's put into total-body thermal therapy.






Versions of this are currently are currently trialed by Dr. Bull for various non BC cancers:
http://www.uth.tmc.edu/thermaltherap...Treatment.html

Previous BC trial with Doxil info: http://www.uth.tmc.edu/thermaltherap...UDoxilIFN.html



Int J Hyperthermia. 2008 Dec;24(8):649-62.
Fever-range whole-body thermal therapy combined with cisplatin, gemcitabine, and daily interferon-alpha: a description of a phase I-II protocol.

Bull JM, Scott GL, Strebel FR, Nagle VL, Oliver D, Redwine M, Rowe RW, Ahn CW, Koch SM.
Source

The Division of Oncology, The University of Texas Medical School at Houston, Houston, TX 77030, USA. joan.m.bull@uth.tmc.edu

Abstract

PURPOSE:

The purpose of the Phase I component of this study was to find the maximally tolerated dose (MTD) of cisplatin administered within a regimen of fever-range whole body thermal therapy (FR-WB-TT), cisplatin, gemcitabine, and low-dose interferon-alpha (IFN-alpha). The Phase II component aimed to assess which cancer diagnoses responded to the regimen, the response rate, and response duration.

MATERIALS AND METHODS:

The protocol design derived from a schedule-optimized preclinical regimen. Drugs were administered together, and also with thermal therapy in a schedule that optimized the therapeutic index. Eligible patients were those with therapy-resistant, metastatic or advanced solid malignancies. Beginning at 40 mg/m(2), the cisplatin dose was escalated by 10 mg/m(2) to the maximally tolerated dose (MTD) in successive cohorts of 3 patients. A treatment cycle consisted of cisplatin on day one, followed by thermal therapy and simultaneous gemcitabine 36 hours later; then a second dose of gemcitabine one week later; and daily IFN- alpha.

RESULTS:

Thirty-seven patients were treated on protocol. The MTD of cisplatin in the thermochemotherapy regimen was established to be 60 mg/m(2). The dose limiting toxicities (DLT) were peripheral neuropathy and ototoxicity. Complete and partial responses combined were 43%. The therapy improved the quality of life of responding patients.

CONCLUSION:

The protocol was well tolerated and was associated with antitumor activity in patients with a variety of advanced metastatic solid tumors. Tumor response occurred with the thermochemotherapy treatment despite treating malignancies that had progressed on the same chemotherapy drugs administered as standard treatment. Notably, good responses were observed in patients with high-grade neuroendocrine and pancreas cancers. This regimen will be tested in a phase II study.

PMID:

18608594

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2362074/

Br J Cancer. 2005 February 14; 92(3): 421–425. Published online 2005 February 8. doi: 10.1038/sj.bjc.6602386.

PMCID: PMC2362074

Copyright 2005, Cancer Research UK
Fever therapy revisited
U Hobohm^1*
1University of Applied Sciences, Bioinformatics, Wiesenstrasse 14, D-35390 Giessen, Germany
^*Author for correspondence: Email: uwe.hobohm@tg.fh-giessen.de


Abstract
The phenomenon of spontaneous regression and remission from cancer has been observed by many physicians and was described in hundreds of publications. However, suggestive clues on cause or trigger are sparse and not substantiated by much experimental evidence. In this review, literature is surveyed and summarised and possible causes are discussed. At least in a larger fraction of cases a hefty feverish infection is linked with spontaneous regression in time and is investigated as putative trigger. Epidemiological and immunological evidence is put into perspective. An online forum to discuss the possible application of fever therapy in the future can be accessed at http://bioinfo.tg.fh-giessen.de/fever-and-cancer.

Spontaneous regressions and remissions from cancer have been recognised since the diagnosis of cancer became a science. Rohdenburg, a medical director at Columbia University, wrote in 1918: ‘It can be definitely asserted that regressive changes varying from a temporary standstill to the complete disappearance of the tumour, whether it be of epithelial or connective tissue origin, may occur at any age period, in either sex, and irrespective of the location of the growth'. On the other hand, large fractions of clinicians over large fractions of the century disregarded the phenomenon or denied that its existence has been proven beyond doubt. Although even a quick glance into the literature must convince us that unexplained healings from cancer happen, it is a rare event and, most importantly, the phenomenon of spontaneous healing in cancer remains almost without clue. Here I survey literature on spontaneous regression and remission and try to align with contemporary immunology and epidemiology.

......

CONCLUSION
A large fraction of spontaneous regressions and remissions described in the literature was preceded by a hefty feverish infection. The hypothesis that fever can have therapeutic value can be brought in line both with successful historical attempts to apply fever using bacterial extracts and with immunological evidence. Putative beneficial effects of fever should as well act preventive, and indeed epidemiological studies show that a personal history of feverish infections reduces the likelihood to develop cancer later.
Immunological strategies to break cancer cell tolerance should be individualised rather than generic. Fever induction will necessarily induce an individual response, which even addresses the problem of antigenic drift in time. Today we should be able to induce and control fever much better than 100 years ago.



20th September 2010

Jordan baffled doctors when his leukaemia vanished, new evidence suggests a remarkable explanation... can a fever cure cancer?

LINK

Several reports, including a recent paper in the Netherlands Journal Of Medicine, have linked a significant number of spontaneous disappearances of leukaemia to fever caused by serious infections.

Now, scientists believe they understand how this might work. There are two theories: the first is that an infection serious enough to provoke a fever response can push the body's immune system into a high-powered, hypersensitive state.

This helps the patient's immune system detect the fact that cancer cells are subtly different from normal healthy cells. It then attacks the tumour cells as though they are infectious invaders.
In everyday life, our immune systems may wipe out many cancer cells unobtrusively, so we never know we were at risk. But, too often, such tumour cells can be sufficiently similar to normal ones that they sneak under the radar of a normally-running immune system and develop into serious cancers.

The other theory is that the high temperature itself attacks and destroys the cancer.

Tantalisingly, Jordan had a mild fever of 38.1c in the days before his clear scans. N ow scientists are trying to harness the power of fever and infection in a controlled way to treat cancer patients.

Researchers in Italy and the U.S., are using the food-poisoning bugs salmonella and listeria to provoke tumour-killing immune responses.

These bacteria are the chief culprits behind the estimated 850,000 cases of food poisoning each year in Britain, around 500 of which are lethal. But scientists are using modified forms of the bacteria that do not cause illness itself.

These are attached to patients' tumour cells in the laboratory, painting them as 'enemies, which is then primed to begin detecting and killing all the tumour cells.

It's hoped that the lab tests will soon be extended to patients themselves.

Food-poisoning bacteria are being used because the body is primed to recognise them and set off major alarms at their presence.

Maria Resign, of the European Institute of Oncology in Milan, is working with neutralised salmonella cells to alert the immune system to skin-cancer cells.

'We did experiments first in mice and then in cancer cells and immune cells from human patients, and found that the salmonella was successfully doing exactly the same job in each case,' she says. 'Now we are ready to go into testing on humans, but we are waiting for authorisation from Italian regulators.'

Meanwhile, in the U.S., drug company Advaxis is doing similar work, using a bioengineered form of listeria, to activate the immune system to combat a broad array of cancers.
Cancer Research UK is helping to fund the company's research trials. One clinical study is already under way, giving the listeria bug to women with cervical cancer. The use of food poisoning bugs is the latest attempt to develop a generation of cancer treatments called immunotherapy drugs - or 'cancer vaccines'.


'We know that cancers do sometimes regress when the immune system is stimulated by an infection'
The idea is to recruit the body's own immune system to fight tumours. In April, the U.S. Food and Drug Administration approved the first immune-stimulating vaccine to treat tumours - Provenge is designed to prime the body's defences to attack prostate cancer.

Another experimental immunotherapy drug, Ipilimumab, is being developed by Bristol-Myers Squibb. It showed some positive results in fighting melanoma in a June trial. Such therapies are still a way off becoming mainstream medicines, but Peter Johnson, chief clinician at Cancer Research UK, is optimistic.

'We are starting to see evidence that this may be a sensible approach to treating cancers,' he says. 'We know that cancers do sometimes regress when the immune system is stimulated by an infection.'

'The complicated challenge for researchers is to work out how you can give a broad stimulus to the immune system and achieve a very specific response - a targeted attack on tumour molecules.

'But we are now seeing, in some cases at least, this kind of thing being achieved with drugs such as Ipilimumab.'

This and other work is also throwing up a fascinating explanation for the spiralling numbers of cancers nowadays; it could be that our immune systems are less on the alert as - thanks to antibiotics, vaccinations and improved hygiene - we have far fewer infections.

Indeed, now some doctors have gone so far as to suggest we should intentionally create fevers in cancer patients. Professor Heinz-Uwe Hobohm, of Berlin's Technical University of Applied Sciences, recently called for controlled fever to be used as part of chemotherapy regimens.
It may kick-start the body to kick out tumours without patients having to take cancer-vaccine drugs.

'Today we should be able to induce and control fever much better than 100 years ago,' he wrote in the British Journal Of Cancer. In fact, in the U.S., Dr Joan Bull, a pioneering oncologist at Memorial Hermann-Texas Medical Centre in Houston, is already heating cancer patients' bodies to boost the immune system.

'We're using a temperature you would get with a bad case of the flu,' says Dr Bull.

Two days after having chemotherapy and immune-boosting drugs, patients are put into an infra-red 'total-body thermal therapy' enclosure nicknamed the 'hot box', for eight hours under sedation.

Their temperature is carefully monitored as it is raised from just under 37c to 40c. 'The fever is giving a startle, a cry for help to the immune system to say, arm yourself, get out here, do something,' Dr Bull says.

She believes if the heat can wake up the immune system, her team can use less chemotherapy and reduce the side-effects which such strong drugs can wreak. Dr Bull is using the experimental therapy on patients with hard-totreat pancreatic cancers and smallcell lung cancers.

'Whole-body fever-range thermal therapy is a gentler therapy than using radiotherapy, which can hit a lot of the body's vital structures,' she says. 'The fever itself is safe; the patient is sedated, not because it hurts, but if you've ever had a fever, you know how crabby you get. We let them sleep.'

[Rich66]

Crit Rev Immunol. 2008;28(2):95-107.
Pathogen-associated molecular pattern in cancer immunotherapy.

Hobohm U, Stanford JL, Grange JM.
University of Applied Sciences, Bioinformatics, Wiesenstrasse 14, D-35390 Giessen, Germany. uwe.hobohm@tg.fh-giessen.de
Observations from different research frontiers--epidemiological data, case studies on spontaneous regressions from cancer, clinical studies, tumor immunology--indicate that exposure by vaccination or infection to pathogen-associated molecular patterns (PAMP) can have beneficial effects on neoplastic diseases, both prophylactically and therapeutically. These effects have not yet been harnessed to their full extent for the prophylaxis and therapy of cancer. Here, we summarize clinical, epidemiological, and experimental data and discuss the role of PAMP in cancer therapy.

PMID: 18540826 [PubMed - indexed for MEDLINE]

[Ellie F]

This is really interesting given the LIFT idea. It appears that an infection/temp may 'wake up' the natural white cells to recognise cancer cells, an ability which they appear to have lost.
Many years ago I attended a lecture by a visiting American onc who speculated that people who developed cancer had immune systems that had gone 'soft' ie not challenged by infection due to cleanliness, antibiotics etc. He was ridiculed and discredited for this hypothesis. Somehow I feel he was on the right track!!
Ellie