Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat. Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood, increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times. Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer. It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy. These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy, chemotherapy, radiotherapy, and surgery. Paradoxically, the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms. This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system. The potential for combination therapy with hyperthermia and chemotherapy, radiotherapy, and surgery is also discussed.

/pdf/cancer-immunity-and-therapy-using-hyperthermia-with-32fr599myf.pdf

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

https://onlinelibrary.wiley.com/doi/pdf/10.1002/adtp.202000267

The Effects of Localized Heat on the Hallmarks of Cancer

Natural killer (NK) cells have been known to enhance the host immune responses against cancer. NK cell number and cytotoxicity in patients with cancer is often low. Therefore, we developed a large-scale ex vivo NK cell expansion method without feeder layers and introduced NK cell-based autologous immune enhancement therapy (AIET). In this paper, we discuss the epidemiological data that show the relationship between NK activity and cancer incidence, monitoring of NK cell number and activity, anti-cancer activities of NK cells in vitro and in vivo and the effects of the combination of expanded NK cells with monoclonal antibody drugs on cancers through antibody-dependent cellular cytotoxicity. Finally, we also present the clinical cases of NK cell-based AIET and the effect of AIET on advanced stage of pancreatic cancer and on various advanced cancers refractory to conventional therapies. NK cell-based AIET might be a useful strategy in the multidisciplinary approach to cancer.

/pdf/nk-cell-based-autologous-immune-enhancement-therapy-aiet-for-2gaxrsjxom.pdf

NK cell-based autologous immune enhancement therapy (AIET) for cancer

Immune cell-based therapies are emerging as a promising tool to tackle malignancies, both solid tumors and selected hematological tumors. Vast experiences in literature have documented their safety and added survival benefits when such cell-based therapies are combined with the existing treatment options. Numerous methodologies of processing and in vitro expansion protocols of immune cells, such as the dendritic cells, natural killer (NK) cells, NKT cells, αβ T cells, so-called activated T lymphocytes, γδ T cells, cytotoxic T lymphocytes, and lymphokine-activated killer cells, have been reported for use in cell-based therapies. Among this handful of immune cells of significance, the NK cells stand apart from the rest for not only their direct cytotoxic ability against cancer cells but also their added advantage, which includes their capability of (i) action through both innate and adaptive immune mechanism, (ii) tackling viruses too, giving benefits in conditions where viral infections culminate in cancer, and (iii) destroying cancer stem cells, thereby preventing resistance to chemotherapy and radiotherapy. This review thoroughly analyses the sources of such NK cells, methods for expansion, and the future potentials of taking the in vitro expanded allogeneic NK cells with good cytotoxic ability as a drug for treating cancer and/or viral infection and even as a prophylactic tool for prevention of cancer after initial remission.

Natural killer cells as a promising tool to tackle cancer-A review of sources, methodologies, and potentials.

Combination of interstitial hyperthermia and radiation brachytherapy has been shown to be effective for treatment of a tumor. After increasing the temperature, the tumor becomes sensitive to radiation dose, and as a result the radiation dose can be reduced. The purpose of this study was to identify the appropriate invasive antenna array which can be effectively used on a deep-seated breast tumor to increase the temperature to more than 42.5°C, and to examine the effect of a smaller cumulative radiation dose of 30 Gy. We have found coaxial-slot antenna array to be the most appropriate for applying hyperthermia on a deep-seated breast tumor. The temperature distributions were measured with a breast phantom, and specific absorption rate (SAR) distributions were calculated using a simulation software. A coaxial-slot antenna array, consisting of two coaxial-slot antennas, separated by 5 mm, and using a microwave power of 15 W increased the temperature of a tumor phantom, in an area of 30 mm in diameter, to over 42.5°C in 30 min. The temperature as well as SAR were observed to have increased more in the tumor tissue than in the other types of tissues which were tested. Thereafter, we have examined the radiation dose distribution of brachytherapy using a treatment planning software. Simulations were conducted on the Computed Tomography image of an anonymous breast tumor patient; the tumorʼs dimensions were 40 mm (length)×30 mm (width). A radiation dose of 30 Gy given in 5 fractions of 6 Gy each, which is lesser than the conventional radiation doses used in external beam radiation therapy, was applied to the tumor. Harm to adjacent tissues is also expected to be minimized due to lower radiation dose. As a result of this study, there is a possibility of local control of deep-seated small breast tumors using a combination of interstitial hyperthermia by using coaxial-slot antenna array to increase the temperature to over 42.5°C and radiation brachytherapy by applying cumulative dose of 30 Gy.

Interstitial Hyperthermia in Combination with Radiation Brachytherapy for Treatment of Breast Tumor

Hyperthermia has been known to enhance the host immune responses against cancer through several mechanisms. One of the mechanisms is sensitization of cancer cells to natural killer(NK)cells through enhancement of NK cell-activating ligands on cancer cells. However,NK cell number and cytotoxicity in patients with cancer is often low. Therefore,NK cell-based adoptive immune cell therapy can be applied for cancer patients after hyperthermia. In this paper,we discuss these findings from our data. Moreover,we present the clinical usefulness of combining hyperthermia,immune cell therapy,and low-dose chemotherapy as palliative treatment for advanced stages of cancer,which are refractory to conventional therapy in the context of NK cell-mediated immune responses.

Effects of Hyperthermia on the Host Immune System : From NK Cell-based Science to Clinical Application

Effects of Hyperthermia on the Host Immune System

The NK cell is a major player in anti-cancer immunity, and hyperthermia augments host immunity against cancer. In cancer patients, NK cell activity is often suppressed. Therefore, when treating cancer patients with hyperthermia, it is desirable to restore the NK cell activity by co-administering a large number of highly activated NK cells that are prepared using a sophisticated cell culture strategy. This chapter describes ex vivo-expanded NK cells used in immunotherapy, the effects of hyperthermia on NK activity, and clinical applications of the combinatory therapy with hyperthermia and NK cells.

Combining Hyperthermia and Immunotherapy: NK Therapy and Hyperthermia

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Effects of Hyperthermia on the Host Immune System : From NK Cell-based Science to Clinical Application

Effects of Hyperthermia on the Host Immune System

Combining Hyperthermia and Immunotherapy: NK Therapy and Hyperthermia