Could heat improve the immune system's response to cancer?
Scientists are applying old ideas in more inexpensive and precise ways
By conservative estimates, the microbes living in each human body outnumber our own cells three to one. Most of these trillions of microbes live in harmonious co-existence with our cells, but occasionally something causes a problem – anything from the flu to Ebola – and the body's immune system races into action.
Like a watchman, the immune system protects us from various infectious diseases with an arsenal of specialized cells: those that act as security cameras, looking for the tell-tale signs of invasions, and those that serve as potent, precise firearms to fight these invading pathogens. Cells such as macrophages and dendritic cells act as the cameras of the immune system, surveilling the body for signs of pathogens and foreign bodies, called antigens. Occasionally, the immune system also senses a danger signal, such as a cell fragment or component of a pathogen, tipping it off to threats. Then the weaponized cells move in and neutralize the targets. (Although in most cases beneficial, the same immune system can also recognize mismatched organ transplants, rejecting and destroying them.) These tools put the immune system in a unique position to fight cancer, acting as a surveillance system for abnormal growths and mutated cells.
Unfortunately, in rare cases tumors can "escape" the surveillance, and, set loose in the body, become potentially deadly. Through a process known as immunoediting, the immune system also promotes the evolution of tumors which are invisible to it, or those that can co-exist within the body by creating an immune suppressive environment.
Treatments for cancer have come a long way from the “one size fits all” surgical approach, which would send every patient to the operating room to have tumors excised. Significant advances in chemotherapy, radiotherapy, and immunotherapy have created many more precise methods of treatment. Today, doctors can draw up personalized treatment plans based on the molecular signature of a specific tumor in a patient. Drawing on a recent revolution in studying the immune system, scientists in the last few years have taken old ideas and found ways to apply them in ever more inexpensive, precise, and exciting ways.
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.
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.
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.