Hyperthermia and immunotherapy: clinical opportunities.

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.