Hyperthermia and cancer immunotherapy

Coley injected inactivated bacteria into patients, like setting off the alarm in a building where the guards had fallen asleep

Using the body’s natural security system against cancer has a long history, beginning in the late 19th century with the experiments of William B. Coley, who is now remembered as the “father of Immunotherapy.” Coley injected inactivated bacteria into the tumors of his patients, activating the immune system in an attempt to direct it to destroy the malignancy – much like like setting off the alarm in a building where the guards had fallen asleep.

Although the practice had early beginnings, for decades scientists lacked a deeper understanding of how the immune system functions, which hindered the development of therapies. Over those years, advances in radiotherapy and chemotherapy caused Coley’s treatments to fall out of favor with many clinicians. However, recent research on how the immune system functions has provided many novel insights, which in turn have helped develop improved treatments.

In the early 1980s, Nobel Prize-winning research into how our bodies produce antibodies (proteins important in detecting foreign bodies) helped scientists recreate this process in a laboratory – driving a revolution in immunotherapy. In 1992, the FDA approved synthetically produced interleukin 2 (IL-2), a molecule that can activate the immune system for the treatment of metastatic melanoma, marking the first time such a method was approved for treating cancer. Currently, dozens of such synthetic antibodies have been approved around the world for treating various malignancies.

Another branch of immunotherapy involves the use of immune cells modified ex vivo (outside of the human body). This treatment has gained prominence in recent years, and entered clinical use. Two such therapies are based on the use of CAR-T cells, which bear specially designed receptors for tumor antigens, and of dendritic cells, which alert other immune system cells to the presence of antigens.

Dendritic cell

Concerns still remain with the use of cell-based therapies, however, and using modified dendritic cells is still an expensive process. New research from the bioengineer Yangqi Ye and a team at North Carolina State University, published late last year, attempted to improve immunotherapies in a surprisingly simple – and inexpensive – way: a local increase in body temperature, called targeted hyperthermia.

These researchers formulated a mixture of a crude, ground-up tumor, combined with a molecule responsible for attracting dendritic cells (GM-CSF), and designed it to ensure a constant and gradual release into the body. They then applied these on a mouse, and induced local hyperthermia at the site. They observed that such a “vaccination” could not only prevent similar tumors in the mouse, but also encouraged the immune system to attack any tumors that had spread to other parts of the body.

The heat helped recruit immune cells to the area, which in turn drew the attention of other kinds of cells, leading to a cascade of immune system activity.

A unique feature of this model was the addition of melanin to the ground-up tumor, one of the pigments responsible for human skin coloration. Melanin is highly efficient at converting radiation energy into heat, and was used to target the hyperthermia to the site of the injection. The researchers suggest that the heat increased the local tissue temperature to around 42°C (almost 108°F), and the subsequent release of pro-inflammatory molecules helped recruit immune cells to area. These cells in turn draw the attention of yet other kinds of immune cells, leading to a cascade of immune system activity around the tumor antigens. The systemic, rather than localized, nature of this activation means the immune system targets not only the primary tumor, but also metastases in other organs around the body.

The use of a simple lysate of the tumor for immunization, in combination with melanin, could prove to be a more economical approach than that used by another recent clinical trial, which used a cocktail of antigens tailored for each patient’s malignancy.

These delayed-release methods, involving melanin and a protein lysate of tumors, still need more study, including a detailed analysis of potential side effects in humans. However, they appear to be a promising new treatment, delivering more economical and personalized treatment strategies than many other widespread methods, especially for treating melanomas – the next step in the advancing science of using the body’s natural defenses to achieve more precise and powerful effects against tumors.

https://massivesci.com/articles/immune-system-cancer-defense-immunotherapy/

J Pak Med Assoc. 2013 Apr;63(4):504-8.

Treating cancer with heat: hyperthermia as promising strategy to enhance apoptosis.

Ahmed K1, Zaidi SF.

Author information

Abstract

The fundamental idea and the effects of heat on cancer cells are well known. However, the results obtained in therapy by hyperthermia (HT) alone have been only partially satisfactory. Treatment at temperatures between .40 and 44 degrees C is cytotoxic for cells in an environment with a low oxygen partial pressure and low pH, conditions that are found specifically within tumour tissue, due to insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied cytotoxic agents will reach such areas in lower concentrations than in well-perfused areas. Therefore, clinically, it is preferred to use hyperthermia in combination with radiation therapy and chemotherapy. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources; regional hyperthermia by perfusion of organs or limbs, or by irrigation of body cavities; and whole-body hyperthermia. Number of studies have reported the combination of thermo-radiotherapy. Consequently, much attention has been focussed on identifying agents among the conventional chemotherapeutic substances that can sensitise tumour cells to hyperthermia-induced damage with minimal effects on normal cells. In this review, we overviewed important mechanisms of hyperthermia-induced apoptosis and the substances which can act as heat sensitisers in cancer therapy.

PMID: 23905451

[Indexed for MEDLINE] Free full text

Send to

J Pak Med Assoc. 2013 Apr;63(4):504-8.

Treating cancer with heat: hyperthermia as promising strategy to enhance apoptosis.

Ahmed K1, Zaidi SF.

Author information

Abstract

The fundamental idea and the effects of heat on cancer cells are well known. However, the results obtained in therapy by hyperthermia (HT) alone have been only partially satisfactory. Treatment at temperatures between .40 and 44 degrees C is cytotoxic for cells in an environment with a low oxygen partial pressure and low pH, conditions that are found specifically within tumour tissue, due to insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied cytotoxic agents will reach such areas in lower concentrations than in well-perfused areas. Therefore, clinically, it is preferred to use hyperthermia in combination with radiation therapy and chemotherapy. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources; regional hyperthermia by perfusion of organs or limbs, or by irrigation of body cavities; and whole-body hyperthermia. Number of studies have reported the combination of thermo-radiotherapy. Consequently, much attention has been focussed on identifying agents among the conventional chemotherapeutic substances that can sensitise tumour cells to hyperthermia-induced damage with minimal effects on normal cells. In this review, we overviewed important mechanisms of hyperthermia-induced apoptosis and the substances which can act as heat sensitisers in cancer therapy.

PMID: 23905451

[Indexed for MEDLINE] Free full text

https://www.ncbi.nlm.nih.gov/pubmed/23905451

Send to

Tumori. 2010 Nov-Dec;96(6):902-10.

The role of hyperthermia in the battle against cancer.

Palazzi M1, Maluta S, Dall’Oglio S, Romano M.

Author information

Abstract

AIMS AND BACKGROUND:

Hyperthermia, the heating of tumors to 41.5-43 degrees C, could be today considered the fourth pillar of the treatment of cancer. Employed for 20 years in Europe, the U.S.A. and Asia, hyperthermia, used in addition to radiotherapy, chemotherapy and surgery, increases both local control and overall survival, restores the chance of the surgery for inoperable tumors and allows a new low-dosage treatment of relapsed cancers previously treated with high radiotherapy dosage without increasing toxicity.

METHODS:

Hyperthermia can be either superficial, produced by a microwave generator, or regional, produced by a radiofrequency applicator with multiple antennas, which emanate a deep focalized or interstitial heating.

RESULTS:

The results are confirmed by phase III randomized trials, with level 1 evidence. A review of the international literature on hyperthermia, the experience of the University Hospital of Verona Radiotherapy Department (Italy) and a summary of the Symposium regarding the Evolution of Clinical Hyperthermia plus Radiotherapy during the Twentieth Congress of the French Society of Radiation Oncology (SFRO) are presented.

CONCLUSIONS:

Hyperthermia is an important treatment modality in cancer treatment and its results are strongly supported by criteria of evidence-based medicine. Fifteen years of experience of the Radiation Oncology Department in Verona confirms the positive results obtained with international prospective trials, with level 1 evidence. Hyperthermia appears to be the fourth pillar beside surgery, radiotherapy and chemotherapy.

Tumori. 2010 Nov-Dec;96(6):902-10.

The role of hyperthermia in the battle against cancer.

Palazzi M1, Maluta S, Dall’Oglio S, Romano M.

Author information

Abstract

AIMS AND BACKGROUND:

Hyperthermia, the heating of tumors to 41.5-43 degrees C, could be today considered the fourth pillar of the treatment of cancer. Employed for 20 years in Europe, the U.S.A. and Asia, hyperthermia, used in addition to radiotherapy, chemotherapy and surgery, increases both local control and overall survival, restores the chance of the surgery for inoperable tumors and allows a new low-dosage treatment of relapsed cancers previously treated with high radiotherapy dosage without increasing toxicity.

METHODS:

Hyperthermia can be either superficial, produced by a microwave generator, or regional, produced by a radiofrequency applicator with multiple antennas, which emanate a deep focalized or interstitial heating.

RESULTS:

The results are confirmed by phase III randomized trials, with level 1 evidence. A review of the international literature on hyperthermia, the experience of the University Hospital of Verona Radiotherapy Department (Italy) and a summary of the Symposium regarding the Evolution of Clinical Hyperthermia plus Radiotherapy during the Twentieth Congress of the French Society of Radiation Oncology (SFRO) are presented.

CONCLUSIONS:

Hyperthermia is an important treatment modality in cancer treatment and its results are strongly supported by criteria of evidence-based medicine. Fifteen years of experience of the Radiation Oncology Department in Verona confirms the positive results obtained with international prospective trials, with level 1 evidence. Hyperthermia appears to be the fourth pillar beside surgery, radiotherapy and chemotherapy.

PMID: 21388050

[Indexed for MEDLINE]

https://www.ncbi.nlm.nih.gov/pubmed/21388050

The extensive experience with the Issels Integrative Immunotherapy has shown Hyperthermia to be a valuable component of integrative cancer treatment.

Hyperthermia or Thermal Therapy is deliberate heating of the whole body or parts of the body for therapeutic purposes. It has in recent years received increasing attention as an adjunct to cancer treatment. Systemic or Whole Body Hyperthermia for cancer and other systemic diseases is now carried out at several university hospital centers in the United States and Europe.

A variety of studies have shown, some of them even provided strong evidence, that systemic hyperthermia can induce:

  • Maturation of Dendritic Cells (3).
  • Dendritic cells to cross-present antigens to CD8þ T cells (4).
  • Prolonged activation of human T-cells (5).
  • Activation of Monocytes and Macrophages (6).
  • Release of Tumor Necrosis Factor a (TNFa) (6).
  • Increase of T-Lymphocytes and Natural Killer Cells (NK Cells) (4,7,8).
  • Stimulate the Innate Immune System (4).

In addition, under the influence of heat, tumor cells will form “heat shock proteins”, effective identifiers of non-healthy cells that appear on the surface of the degenerated cells. The body’s immune system detects these proteins as extraneous cells, triggering its immune cells to fight the cancer cells.

Thus systemic hyperthermia is now widely accepted as an effective, nontoxic adjuvant to immunotherapy as well as standard cancer therapies.

History on the Use of Hyperthermia

The use of heat to treat disease goes back to ancient times. Ancient Greek physicians recognized the therapeutic value of fever. In the nineteenth century several German physicians observed regression or cure of sarcomas in patients who suffered prolonged high fevers due to infectious diseases. Nineteenth century New York physician, William Coley, achieved cancer cures by administration of bacterial endotoxins, now known as Coley’s Mixed Bacterial Vaccine, and attempted to create standardized preparations of these pyrogens (1).

Since 1951, Josef M. Issels, MD, the founder of our Integrative Oncology programs, consistently administered fever therapy to thousands of his cancer patients with remarkable results. He trained his followers in this treatment and our present team of doctors have extensive experience in administering fever therapy for qualified patients. It is always integrated into our immunobiological core treatment.

Additional Information on Medical Hyperthermia Treatment

Apart from the induction of biological fever by pathogens or toxins, all methods of hyperthermia involve transfer of heat into the body from an external energy source. Different types of energy may be used to apply heat including microwave, radio frequency and ultrasound.

It was in the first decades of the twentieth century that the biological effects of elevated body temperature were better understood and numerous devices were developed to apply therapeutic heat to the whole body. After a shift in focus to local and regional hyperthermia (which treat only a specific tissue, limb or body region), there is now growing interest in systemic hyperthermia in view of its advantages.

The goal of systemic hyperthermia is to reproduce the beneficial effects of fever (2). Typically, core body temperatures of 40-41 Celsius are induced for 1-2 hours, or alternatively 39-40 Celsius for 4-8 hours.
By the application of heat to the whole body, systemic hyperthermia is designed to treat systemic disease conditions including cancer. Tumors have a higher thermal sensitivity than normal tissues because of abnormal vasculature, anaerobic metabolism (acidosis) and nutrient depletion.

Our patients who are eligible for this treatment have the option to receive fever treatment in the form of Coley’s Mixed Bacterial Vaccine or systemic hyperthermia in the form of the following specialized technique. Blood is extracted in a constant flow and heated while it also flows through an ozonification and ultraviolet light device. Before the hyper-oxygenated heated blood is returned to the body, it passes through a detoxification filter to be cleansed of toxins and cellular debris. Throughout this procedure the patient is continually monitored by trained staff and by the device.

References

Nauts HC. Bacterial pyrogens: beneficial effects on cancer patients. In: Gautherie M, Albert E, editors. Biomedical Thermology, Progress in Clinical Biological Research. New York:Alan R. Liss; 1982. p 687-696.

Issels RD, Wilmanns W, editors. Recent Results in Cancer Research, Vol. 107: Application of Hyperthermia in the Treatment of Cancer.Berlin/Heidelberg: Springer Verlag; 1988.

Ostberg JR, Repasky EA. Emerging evidence indicates that
physiologically relevant thermal stress regulates dendritic cell function. Cancer Immunol Immunother [Epub ahead of print]; Apr 28, 2005.

Manjili MH, et al. Subjeck, Cancer immunotherapy: stress proteins and hyperthermia. Int J Hyperthermia 2002;18(6): 506-520.

Atanackovic D, et al. 41.8 degrees C whole body hyperthermia as an adjunct to chemotherapy induces prolonged T cell activation in patients with various malignant diseases. Cancer Immunol Immunother Epub 2002 Oct 18 2002;51(11-12):603.

Barni S, et al. Lysosomal exocytosis induced by hyperthermia:
a new model of cancer death. III. effect on liver metastasis. Biomed Pharmacother 1996;50:79-84.

Burd R, et al. Tumor cell apoptosis, lymphocyte recruitment and tumor vascular changes are induced by low temperature, long duration (fever-like) whole body hyperthermia. J Cell Physiol 1998;177(1):137-147.

Shen RN, et al. Whole-body hyperthermia decreases lung metastases in lung tumor-bearing mice, possibly via a mechanism involving natural killer cells. J Clin Immunol.

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