ICHO congress - Personal Review
Stefan Heckel-Reusser, December 2021
At the International Congress on Hyperthermic Oncology 2021 the topics relevant to our products had a high priority.
I. Superficial hyperthermia combined with re-irradiation:
Akke Bakker (UMC Amsterdam) had shown in a systematic review a positive correlation of temperature and thermal dose with clinical outcome in inoperable local recurrences of breast cancer ("macroscopic disease"). In a new retrospective analysis of 112 patients treated postoperatively in Amsterdam ("microscopic disease"), local control after 3 years was 92% in the group with a higher thermal dose and 74% with a lower thermal dose. Akke Bakker suggested invasive temperature measurement as quality assurance even in routine use.
Markus Notter showed from the 170 "macroscopic disease" patients published in Cancers in 2020, a subgroup of 39 patients with lesions deeper than 15mm, where the intratumoral temperatures achieved are usually below 40°C. Surprisingly, this subgroup did not show a worse response to therapy than the overall group.
One explanation could lie in the sequence and timing of the combined HT/re-RT. In all 170 patients, HT was performed before re-RT, and the time gap between HT and re-RT was just a few minutes. At this, oxygenation of hypoxic areas may play a greater role in radiosensitisation. This mechanism is already stimulated from about 39°C and too high temperatures (from about 43°C) can even be counterproductive. In almost all of the studies on which the review by Bakker et al. was based, the sequencing was reversed and the time interval between re-RT and HT was much longer. Here, the most important radiosensitising mechanism may be inhibition of DNA repair, which requires temperatures > 41°C.
Thomsen presented new measurements from the University Medical Center Freiburg on the increase in pO2 caused by wIRA irradiation in healthy volunteers: For example, at a depth of 13mm, the pO2 value increased from 46 to 81 mmHg and was still 72 mmHg 15 minutes after the end of wIRA irradiation.
II. Whole-Body Hyperthermia
During the digital International Congress on Hyperthermic Oncology 2021, the topic of whole-body hyperthermia (WBH) was much more prominent than in STM and ESHO meetings of the last few years.
In the presidential session, Sharon Evans gave an excellent immunological overview on hyperthermia. Stimulating effects can be found at all steps of anti-cancer immune response, from release of cancer antigens, antigen presentation, priming and activation, trafficking of T cells and infiltration into tumors, to recognition and killing of cancer cells by T cells. The required temperatures are often in the fever range and well applicable in WBH treatment protocols.
Ralf Kleef, Wien/Budapest, presented his novel combined treatment protocol including low-dose checkpoint inhibitors , individually titrated IL-2 treatment under taurolidine protection, locoregional hyperthermia and fever-range WBH. A case series of 131 stage IV cancer patients has recently been published with encouraging efficacy and toxicity results. In this combined protocol, low-dose checkpoint inhibitors demonstrated a better safety profile without compromising the therapeutic efficacy. Kleef hypothesises that a fully activated and "de-blocked" T-cell which is further stimulated by IL-2 can perform optimal tumor cell killing if it can operate in fever mode.
There is a new interest in extreme WBH. The Belgic company ELMEDIX presented a new device "HyperTherm" using a hot air cabinet. 6 dogs bearing different tumour entities were treated under general anesthesia. It took 2,5 hours to reach 41.5°C and this temperature was kept stable for 8 hours with uniform temperature in liver, rectum, and tumour. WBH was combined with chemotherapy (simultaneously) or radiotherapy (after WBH) and overall well tolerated. Follow-up studies are in preparation. It is - as far as we know - the first approach of a long-duration extreme WBH.
The ASHO award winner Xunfan Shao from Guangzhou Medical University, China, reported on clinical WBH studies. His working group has changed from applying extreme WBH with general anesthesia (41.8°C x 120min.) to WBH with deep sedation (41°C x 120min.) to fever-range WBH (FR WBH) under concious conditions (39.5 - 40.5°C x 120min.). A retrospective study using FR WBH combined with chemoradiotherapy resulted in an improved Overall Survival of patients presenting with advanced nasopharyngeal carcinoma (NPC). A clinical phase III study is in planning. In addition, they are going to carry out clinical research on WBH combined with immunotherapy for patients with metastasis from NPC.
The IOZK (Immun-Onkologisches Zentrum Köln) has developed a "Individualized Multimodal Immunotherapy" (IMI) based on personalized vaccination and including virotherapy and hyperthermia. In a retrospective analysis, reported by Stefaan van Gool, fever-range WBH (38.5 - 39.5°C, 45 - 120 min.) using heckel WBH systems, had a positive effect to restore NK cell function. The restored NK cell function was maintained during the further disease course in 36% of the patients. These positive effects were not observed in patients who did not receive WBH (most of them due to lack of time or financial ressources, not due to WBH contraindications). He concluded that WBH could be recommended as modulatory immunotherapy to support NK cell function.
Bettina Weigelin from University of Tübingen presented various effects of fever-range HT on Cytotoxic T Lymphocytes (CTL) effector function, e.g., by stabilizing CTL contacts and impairing cancer cell recovery from CTL-mediated sublethal damage. Using multiphoton intravital microscopy, the kinetics of anti-tumor immune activity can be shown in live tissue of mice. Interestingly, the immune stimulating effect of fever-range HT does only lead to a successful anti-tumor effect on the base of an activated anti-tumor response which must first be induced by other therapies, e.g., adoptive T cell therapy. However, in these combined treatment protocols, the benefitial role of fever-range HT is significant. Comparing fever-range HT of 38.5 and 39.5°C, the anti-tumor immune stimulation was interestingly quite similar. For us, the research of Bettina Weigelin and her group is a most important contribution to develop fever-range WBH as an essential module of combined treatment protocols including cytotoxic therapies and immunotherapies.