Hyperthermia in Cancer Treatment

How Dr. William Coley’s Discovery Changed Cancer Care

Here’s the story, in 1890, Elisabeth “Bessie” Dashiell, the 17 year old friend of JD Rockefeller Jr. saw Dr. Coley for a hand injury that was progressively worsening. He diagnosed her with aggressive round cell sarcoma and amputated her arm below the elbow. The cancer spread and she succumbed to the disease in 1891. Distraught by this outcome, Dr Coley searched the records of Memorial Hospital in New York until he found a case similar to Bessie’s but with a different outcome. The patient was discharged from the hospital showing no evidence of disease. It was discovered that he had developed a post-surgical infection known as erysipelas, which led to a high fever. A few days later, his tumor had spontaneously shrunk. Years later, Coley tracked the patient down and he was still alive.

Coley’s Toxin: The Foundation of Modern Immunotherapy

Coley’s toxin was a “safe” toxin created to induce similar therapeutic effects that activated the immune system and mimicked chills and fever. This was used for years with lasting remissions but was discredited by the American Medical Association (AMA) in favor of radiation and later chemotherapy. In 1962, Coley’s toxin became illegal and the FDA would not recognize it as a proven drug. Coley’s use of his toxin gave birth to modern day immunotherapy.\

Modern Hyperthermia Therapy in Cancer Treatment

Today, to orchestrate a fever, hyperthermia is used. Hyperthermia involves subjecting cancerous tissues and the body to temperatures that exceed physiological levels as high as 113°F. This process aims to damage and destroy cancer cells while minimizing harm to surrounding healthy tissues. Higher temperatures can be achieved in local hyperthermia compared to whole-body hyperthermia (WBH). The purpose of WBH is to raise the body’s core temperature to a fever-like state (typically between 104°F and 107°F or 40°C and 41.5°C) for a controlled period of time.

The Science of Heat and Cancer Cells

Hyperthermia involves raising the temperature of cancerous tissue to a level that damages or kills cancer cells, while minimizing harm to healthy tissue. Cancer cells are often more sensitive to heat than normal cells for several reasons:

• Poor blood supply: Tumors often have a disorganized and inadequate blood supply, making it difficult for them to dissipate heat effectively.
• Acidic microenvironment: HT can affect the microenvironment surrounding cancer cells by altering tumor vasculature, affecting immune cell infiltration, influencing cytokine expression, and impacting tumor metabolism.
• “Cold” to “Hot” Tumors: By regulating the tumor microenvironment, hyperthermia can transform “cold” tumors (tumors with low immune cell infiltration) into “hot” tumors (tumors with high immune cell infiltration), creating a more favorable response to the class of immunotherapy medications called immune checkpoint inhibitors.
• Defective DNA repair mechanisms: Cancer cells frequently have impaired DNA repair and protein synthesis mechanisms, making them more vulnerable to heat-induced damage.
• Heat Shock Proteins (HSP): a family of highly conserved proteins that are expressed in response to various cellular stresses, including heat, oxidative stress, and glucose deprivation and play a crucial role in maintaining cellular homeostasis. However, in the context of cancer, Heat Shock Proteins are over-expressed and hyperthermia causes cancer cells to release these heat shock proteins (HSPs) thereby attracting immune cells including T cells and dendritic cells to the tumor site.
• Cytokine Production: Hyperthermia can enhance the production of pro-inflammatory cytokines, which in turn activates immune cells that specifically target and destroy cancer cells.
  
  

Hyperthermia and the HSP Response

When cells are exposed to elevated temperatures, they undergo a stress response, leading to increased expression of Heat Shock Proteins. The response is complex:

• Initial Protection: Initially, the increased Heat Shock Protein expression can protect regulating the tumor microenvironcancer cells from the damaging effects of heat, contributing to thermotolerance.
• Sensitization with Prolonged Exposure: However, prolonged or sufficiently high hyperthermia can overwhelm the Heat Shock Protein system. The damaged proteins then aggregate, triggering apoptosis, leading to cell death. Additionally, hyperthermia can increase the immunogenicity of cancer cells, making them more susceptible to immune destruction.
  
  

The interplay between hyperthermia and Heat Shock Proteins (HSPs) can be exploited to improve cancer treatment. Combining hyperthermia with HSP inhibitors can disrupt the protective effects of HSPs, rendering cancer cells more vulnerable to heat-induced damage.

Natural HSP Inhibitors

HSP90 is a heat shock protein essential for the growth and survival of cancer cells. Certain herbal compounds have the potential to hinder the proliferation and viability of these cancer cells by inhibiting HSP90.

• Epigallocatechin-3-gallate (EGCG):
  A primary component of green tea, EGCG exhibits inhibitory effects against HSP90.
• Celastrol:
  Sourced from the Chinese herb Tripterygium wilfordii or Thunder God Vine, celastrol is a powerful inhibitor of HSP90.
• Quercetin:
  A flavonoid found in many plants, quercetin can inhibit the expression of HSP proteins, such as HSP27, HSP70, and HSP90 by destabilizing and promoting cancer cell death.
• Curcumin:
  Extracted from turmeric, curcumin not only inhibits HSP90 but also possesses additional benefits, such as inhibiting NF-κB activation.
• Ascorbic Acid:
  Vitamin C can induce an oxidative cleavage of Hsp90 in cancer cells, potentially leading to its inactivation.
• Myricetin:
  A flavonoid found in fruits and vegetables, myricetin inhibits HSP90 leading to program cell death.
  
  

Types of Hyperthermia

Hyperthermia can be delivered in several ways, depending on the location and extent of the cancer:

• Local Hyperthermia: Targets a specific area, such as a tumor on or near the skin. Methods include radiofrequency ablation (RFA) and microwave hyperthermia.
• Regional Hyperthermia: Treats larger areas, such as an entire organ or limb. Techniques include isolated limb perfusion and deep tissue hyperthermia.
• Whole-Body Hyperthermia: Raises the body temperature to treat widespread cancer. This can be achieved through various methods, one of which is Radiant Heat Whole Body Hyperthermia using non-ionized infrared radiation.
  
  

Radiant Heat Whole Body Hyperthermia

Radiant heat whole-body hyperthermia involves using infrared lamps to gently raise the body’s core temperature. Under supervision, the patient lies in a specialized chamber for several hours as the heat is carefully controlled and monitored. This method is often used in conjunction with vitamin C.

Hyperthermia enhances the anti-cancer activity of vitamin C by increasing blood flow to the tumor mass. It also makes cancer cells more susceptible to the cytotoxic effects of chemotherapy including insulin potentiated chemotherapy. In addition to direct cancer cell damage, radiant heat whole-body hyperthermia can also stimulate the immune system and modulate the tumor microenvironment (TME), potentially leading to a more robust anti-tumor response.