Despite significant advancements in the development of novel therapies, cancer continues to stand as a prominent global cause of death. In many cases, the cornerstone of standard-of-care therapy consists of chemotherapy (CT), radiotherapy (RT), or a combination of both. Notably, hyperthermia (HT), which has been in clinical use in the last four decades, has proven to enhance the effectiveness of CT and RT, owing to its recognized potency as a sensitizer. Furthermore, HT exerts effects on all steps of the cancer–immunity cycle and exerts a significant impact on key oncogenic pathways. Most recently, there has been a noticeable expansion of cancer research related to treatment options involving immunotherapy (IT) and targeted therapy (TT), a trend also visible in the research and development pipelines of pharmaceutical companies. However, the potential results arising from the combination of these innovative therapeutic approaches with HT remain largely unexplored. Therefore, this review aims to explore the oncology pipelines of major pharmaceutical companies, with the primary objective of identifying the principal targets of forthcoming therapies that have the potential to be advantageous for patients by specifically targeting molecular pathways involved in HT. The ultimate goal of this review is to pave the way for future research initiatives and clinical trials that harness the synergy between emerging IT and TT medications when used in conjunction with HT.

Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood. Therefore, we aim to assess the direct cytotoxic effect of HT in PDAC cells as monotherapy or in combination with chemotherapeutics. Different temperatures (37-, 40.5-, 41-, and 41.5 °C) and durations (6-, 12-, and 24 h) were tested in PDAC cell lines (BxPC-3, Capan-1, Capan-2, PANC-1, and MIA-PaCa-2). Different concentrations of gemcitabine, 5-fluorouracil, and cisplatin were also tested in these conditions. The impact on cell metabolic activity was determined by an MTS assay. Enhancement of chemosensitivity was assessed by a reduction in half-maximal inhibitory concentration ($I{C}_{50}$). HT and chemotherapeutics interactions were classified as antagonistic, additive, or synergistic using the combination index. HT inhibited cell proliferation in a cell type, temperature, and duration-dependent manner. The induction of apoptosis was seen after 6 h of HT treatment, eventually followed by secondary necrosis. The HT and CT combination led to an $I{C}_{50}$ reduction of the tested CT. At 12 h of HT, this effect was between 25 to 90% and reached a 95% reduction at 24 h. The additive or synergistic effect was demonstrated in all cell lines and chemotherapeutics, although, again, this depended on cell type, duration, and temperature. HT is cytotoxic and enhances the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells. This result was further confirmed by the decrease in the expression of RRM2, TS, and ERCC1 in BxPC-3 and Capan-2 cells. These observations warrant further study in specific subsets of PDAC patients to improve their clinical outcomes.

The use of heat to treat various diseases is called hyperthermia treatment (HT). Since the 1970s, the anti-cancer effects of HT have been investigated. Different HT techniques can be categorized as...

Aim: In oncology, thermal therapy is the application of external heat to fight cancer cells. The goal of whole-body thermal treatment (WBTT) is to raise the patient’s core temperature to 39–42 °C, and represents the only thermal treatment modality that can act on both the primary tumor and distant metastases. However, WBTT carries potential risks for toxicity when applied without accurate thermometry and monitoring. Methods: ElmediX has developed a medical device, HyperTherm, to deliver long-term controlled and accurate WBTT (41.5 °C, up to 8 h). The safety of the device and thermal treatment protocol was initially evaluated in minipigs, and we present the confirmation of tolerability of WBTT in dogs with advanced cancer, in combination with a reduced dose of radiotherapy or chemotherapy. Results: Thermometry in liver, rectum, and tumor confirmed a homogeneous heating of these body parts. Monitoring of clinical parameters showed acceptable and reversible changes in liver, cardiac, muscle and coagulation parameters, as was expected. Combination of WBTT with both radiotherapy and chemotherapy only caused some low-grade adverse events. Conclusion: We conclude that our findings support the safe use of HyperTherm-mediated WBTT for canine patients with advanced malignancies. They also tend to support a genuine therapeutic potential for long-term WBTT which needs to be confirmed on a larger dog patient population. Combined with previously reported safety results in minipigs, these contribute to support the ongoing clinical evaluation of WBTT in advanced human cancer patients.

Purpose: Whole-body hyperthermia (WBHT) is a promising therapy for advanced malignancies, including metastatic pancreatic ductal adenocarcinoma (PDAC). This first-in-human study evaluated the safety and tolerability of repeated WBHT sessions at 41.50°C for various treatment durations and in combination with standard-of-care chemotherapy regimens. Patients and Methods: Twelve patients with advanced solid tumors, primarily metastatic PDAC, completed the study. WBHT was administered using an innovative medical device (TempoCure, ElmediX) as monotherapy or with standard-of-care chemotherapy in escalating durations of 2, 4, and 6 hours, in four cohorts. Safety was assessed through adverse event (AE) monitoring, serious AE (SAE) reporting, and comprehensive clinical and laboratory evaluations up to a 10-week follow-up. Tolerability was evaluated according to whether patients were able to complete all planned WBHT cycles, with or without concomitant chemotherapy, without the need for dose modifications or treatment interruptions. Results: The WBHT treatment was well tolerated, with most patients completing scheduled treatments despite advanced disease. The most frequent AEs were fatigue, hypokalemia, nausea, and diarrhea. Initial decubitus ulcers led to improved patient handling protocols. No clear increase in AE or SAE incidence was associated with longer WBHT durations or chemotherapy combination. The trend toward fewer AEs in later treatments likely reflects a procedural learning curve. Conclusions: WBHT administered with the TempoCure system at 41.50°C for 2, 4, and 6 hours is safe and tolerable alone or in combination with chemotherapy, in patients with advanced cancer refractory to prior treatments. These findings support further investigation in upcoming randomized trials designed to evaluate efficacy in metastatic PDAC. Significance: The MATTERS trial demonstrates that WBHT at 41.50°C, delivered with the TempoCure device, is a safe and well-tolerated treatment for advanced malignancies, particularly in patients with refractory metastatic PDAC. These findings support the integration of WBHT with standard chemotherapy regimens, paving the way for future efficacy trials aimed at improving therapeutic outcomes in challenging cancer populations.

Representativeness of Study Participants