Hyperthermia and immunotherapy: clinical opportunities

Abstract

Hyperthermia holds great promise to advance immunotherapy in the treatment of cancer. Multiple trials have demonstrated benefit with the addition of hyperthermia to radiation or chemotherapy in the treatment of wide-ranging malignancies. Similarly, pre-clinical studies have demonstrated the ability of hyperthermia to enhance each of the 8 steps in the cancer-immunotherapy cycle including stimulation of tumor-specific immunity. While there has been an extensive recent focus on augmenting immunotherapy with radiation, surprisingly to date, there have been no clinical trials assessing the combination of hyperthermia with immunotherapy. The study of hyperthermia with immunotherapy is particularly compelling when considered in the context of a new treatment paradigm for this anti-neoplastic modality. Novel concepts include ease of treatment including elicitation of the tumor-specific response of not requiring whole tumor heating, potentially shorter treatment time, better treatment tolerance as opposed to other multi-agent approaches to immunotherapy and the ability to apply heat repeatedly with immunotherapies, unlike ionizing radiation. Several questions remained with regard to clinical integration which can be readily addressed with thoughtful clinical trial design building upon lessons learned at the bench and from clinical trials combining radiation and immunotherapy. Examples of promising avenues for clinical investigation of hyperthermia and immunotherapy including melanoma, bladder, and head and neck cancers are reviewed. In summary, there is a present convergence of factors in oncology that compel further investigation of the integration of hyperthermia with immunotherapy for the benefit of cancer patients.

Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

“…High fever-range hyperthermia has been successfully used in clinical oncology for complementing radiation-, chemo-, or even molecular-targeted therapies [ 1 , 2 , 3 , 4 ]. Loco-regional hyperthermia is thought to inhibit DNA repair enzymes and increase oxygen supply within cancers to sensitize hypoxic tumor cells for γ-irradiation-induced cell death, e.g., in recurrent breast cancer, locally advanced cervical cancer, or head and neck cancer [ 5 , 6 , 7 ].…”

Clinical study of modulated electro‑hyperthermia for advanced metastatic breast cancer

“…Therefore, many patients and medical doctors who continue to treat various types of cancer, including advanced pancreatic cancer and other advanced cases, without further conventional treatment options are looking for a more effective therapeutic method, including the safe and secure hyperthermia treatment. Based on these backgrounds, mEHT is conducted in accordance with basic and clinical research data, which is based on the cellular selection of tumor cells, inducing programmed cell death (apoptosis), in various cancer cells by causing a temperature gradient and prompting extrinsic pathways to produce damage-associated molecular patterns (27) and immunogenic cell death (28,29), thereby producing tumor-specific immune reactions (30) and an abscopal effect (31). The inhibition of protective autophagy via sublethal hyperthermia in hepatocellular carcinoma has been shown to enhance hyperthermia-induced apoptosis via the ATP/AMPK/mTOR signaling pathway (32).…”

Exploring the rationale for thermotherapy in COVID-19

“…The immune system is characterized for being inducible by diverse stimuli, with several possible routes of response according to individual factors which have not been fully characterized yet. Fever-range temperatures (38-41 C) are able to alter the immune response at diverse levels, including both the innate and adaptive immune responses [36][37][38].…”