Hyperthermia as an integral part of immunotherapy

Regional hyperthermia has clearly established itself as a potent amplifier of radiation therapy with scientifically proven evidence. It also offers a positive benefit/side effect ratio in combination with many chemotherapies. In contrast, the potential role of hyperthermia in complementing immunological therapy concepts has not been explored in the same detail,
although hyperthermia per se represents an immunologically stimulating measure based on its ability to elevate the tissue temperature within a target corridor resembling fever. This article discusses the associated arguments in further detail.

At first glance, the rationale of newly emerging immunotherapies (checkpoint inhibitors and CAR-T therapies) has a different starting point. Thus, the efficacy of checkpoint inhibitors is based on eliminating the inhibition exerted by tumor cells on the T lymphocytes of the adaptive immune system. Antigen-presenting cells that have come into contact with a tumor cell are no longer suppressed in their activity, which allows for specifically training naive, undifferentiated T lymphocytes so they can target such tumor cells with precision. The associated mechanism involves small molecules in the cell membranes. In the first generation of this category, the monoclonal antibody ipilimumab, a blockage of CTLA-4 virtually shuts down the inhibitory receptors CD80/CD86 in antigen-presenting cells and CD28 on the T cells, which enables interactions between the antigen-presenting cells and T cells at these checkpoints in the lymph nodes. As a result, the T cells are activated in such a way that they can find and attack their target in the tissue.
The mechanism in the other known antibodies, nivolumab and pembrolizumab, is slightly different, but follows the same principle and effect. The cell membrane of activated T lymphocytes includes the so-called programmed cell death protein 1 (PD-1). When another protein (PD-L1) comes into contact with this receptor, this T cell is deactivated. PD-L1 is typically secreted by antigen-presenting cells to keep their own T cells in check and keep them from proliferating. However, it has been discovered that tumor cells are able to generate this PD-L1 in order to protect themselves. The antibody prevents exactly this deactivation, which keeps this T cell active.

These therapeutic approaches are problematic for their possible side effects, which may result from an immune response that can no longer be down-regulated, potentially leading to excessive autoimmune reactions.

How can hyperthermia support these processes?
The potential of co-adjuvant therapy with hyperthermia results from the following three key considerations:
a. General immunological stimulus based on increased temperature
b. Improved matrix access (so-called lymphatic trafficking) and
c. Targeted support for the adaptive immune system.

Re a. General immunological stimulus
It can be said for all specifically targeted therapies that any assistance for our entire immune system (whether adaptive or primary) is beneficial for patients. As a natural measure in addition to nutrition, moderate exercise and phases of relaxation, a temperature stimulus is helpful and – if properly applied – has no adverse side effects.
G. Multhoff was able to prove that the heat shock proteins generated and distributed by hyperthermia are valuable stimuli for natural killer cells. Because our immune system is more effective in an elevated temperature range, fever has evolved as a helpful tool to support this natural response.
The experience of many years has shown that regional electro-hyperthermia can also be effective in situations of chronic inflammation. The blockage of anti-inflammatory immune checkpoints is a significant side effect that sometimes restricts the treatment with checkpoint inhibitors because it makes overreactions of the immune system more likely, which can cause a wide range of adverse autoimmune side effects. Might EM hyperthermia be able to mitigate this effect? There are currently no studies or preclinical research projects on this topic, but when we look at the analogy to the influence on chronic inflammation, would it not appear obvious that there might be similar potential here? Although that question is of course somewhat speculative, it deserves further examination.

Re b. Lymphatic trafficking
The new targeted immunotherapy strategies are based on the adaptive immune system and particularly, on specifically activated T lymphocytes. These involve a variety of cell movements in the body, from the tumor to the lymph node and back as well as within the matrix in search of tumor cells that may already have scattered. The protagonists are antigen-presenting cells, dendritic cells and natural T cells. Regional hyperthermia can support this process in several ways:

  • The heat subtly expands the target tissue, with the valuable effect that the interstitial pressure in the matrix decreases and lymphatic cells can move more easily.
  • Blood vessels and their ramifications also expand, which creates more volume for absorption.
  • Finally, the subtle expansion of vascular walls in the target area also enhances the permeability of the blood vessels, which is relevant because the target area is located largely outside of the blood vessel system.

Re c. Targeted support for the adaptive immune system
The first important step that helps antigen-presenting cells to recognize a suspicious tumor cell is more or less considered a given, but is anything but trivial. All options to make tumor cells more recognizable are valuable contributions to therapeutic success, and that’s precisely where hyperthermia can be of value!
Due to their fast growth, tumor cells are frequently more susceptible to adverse environmental conditions than normal cells. They frequently have a simpler and less efficient energy utilization process (Warburg effect) and are more prone to stress. Heat is a form of stress. Even a temperature increase of one or two degrees Celsius generates stress proteins, the so-called heat shock proteins (HSP). While this process takes place in all cells as a general rule, the expression in the cell membrane of tumor cells appears to be significantly higher (Multhoff, Gaipl). These HSPs exposed at the cell membrane – the effect was investigated with HSP70 and HSP90 proteins – are now a detectable signal both for the adaptive immune system and an “EAT ME” signal for the natural killer cells of the primary immune system.


The increased density of HSPs in the matrix also emits a strong signal for the increased activity of antigen-presenting cells and dendritic cells in the target area.
Heat or a temperature gradient caused by hyperthermia also selectively has a more specific effect on tumor cells, which makes them more easily recognizable compared to normal cells. This effect significantly reinforces the necessary initial condition of selective identification of malignant cell material.
Optimized synergy with selective radiotherapy
An additional effect may occur if a selective radiation dose were to be added to the target area in this context. Radiation therapy primarily causes necrotic cell death in addition to apoptotic elimination. The necrotic death of cells in turn leads to a considerably stronger trigger for an adaptive immune response. A combination with hyperthermia (Frey et al) would be ideal to further increase the relative portion of necrotic cells.

This strategy would require a protocol that differs from the typical application of radiotherapy. Since the radiation damage of daily fractionation would also affect APC cells, dendritic cells and the subsequent infiltration of T cells, a single, higher-dose radiation, to be repeated after 8-10 days if necessary, would be optimal.

Summary
Regional hyperthermia has rightly earned a reputation as a potent sensitizer, both for radiation therapy and for many, but not all, chemotherapies. Hyperthermia itself also has a positive effect on the body’s immune system. That makes the idea that this complementary thermotherapy option is synergistically conducive to the new generation of immunotherapies quite plausible. It can be expected that studies will provide the necessary evidence for this concept in the years to come.
Hyperthermia still has vastly more potential than is currently acknowledged in clinical practice. However, this perception is slowly changing, year after year, and a level of acceptance has already been achieved, at least in combination with radiotherapy. The same potential also appears to exist in combination with the new generation of immunotherapies.

Martin Rösch

The expertise of Martin Rösch has been closely linked to Celsius42 since the company's founding. As a formally independent contract employee, he has been dedicated to questions of clinical application for many years. He cooperated with customers – in particular with Dr. Hüseyin Sahinbas – to perform preclinical temperature tests and helped to design performance profiles. Moreover, he contributed input and advice on study designs and for many years gathered experiences in customer visits and in discussions with users of our and other hyperthermia systems. Martin Rösch has been an invited speaker on the topic of hyperthermia at oncology conventions in more than a dozen countries and has published articles on the topic in peer-reviewed journals.

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