Abstract
BackgroundThere is an increasing interest in local tumor ablative treatment modalities that induce immunogenic cell death and the generation of antitumor immune responses.MethodsWe report six recurrent glioblastoma patients who were treated with intracavitary thermotherapy after coating the resection cavity wall with superparamagnetic iron oxide nanoparticles (“NanoPaste” technique). Patients underwent six 1-h hyperthermia sessions in an alternating magnetic field and, if possible, received concurrent fractionated radiotherapy at a dose of 39.6 Gy.ResultsThere were no major side effects during active treatment. However, after 2–5 months, patients developed increasing clinical symptoms. CT scans showed tumor flare reactions with prominent edema around nanoparticle deposits. Patients were treated with dexamethasone and, if necessary, underwent re-surgery to remove nanoparticles. Histopathology revealed sustained necrosis directly adjacent to aggregated nanoparticles without evidence for tumor activity. Immunohistochemistry showed upregulation of Caspase-3 and heat shock protein 70, prominent infiltration of macrophages with ingested nanoparticles and CD3+ T-cells. Flow cytometric analysis of freshly prepared tumor cell suspensions revealed increased intracellular ratios of IFN-γ to IL-4 in CD4+ and CD8+ memory T cells, and activation of tumor-associated myeloid cells and microglia with upregulation of HLA-DR and PD-L1. Two patients had long-lasting treatment responses > 23 months without receiving any further therapy.ConclusionIntracavitary thermotherapy combined with radiotherapy can induce a prominent inflammatory reaction around the resection cavity which might trigger potent antitumor immune responses possibly leading to long-term stabilization of recurrent GBM patients. These results warrant further investigations in a prospective phase-I trial.
Highlights
For recurrent glioblastoma patients, there is increasing interest in local tumor ablative treatment modalities that can induce immunogenic cell death leading to the generation of tumor-specific immune responses.Hyperthermia in tumor tissues induced by superparamagnetic iron oxide nanoparticles (SPIONs) subjected to an alternating magnetic field (AMF) has been evaluated by various ex-vivo and in-vivo experiments including assessments of biocompatibility, depot stability, and preclinical efficacy [1–7]
In preclinical glioma models, local hyperthermia generated by SPIONs was shown to induce potent antitumor immune responses [8–10]
Prominent leucocyte infiltrates could be observed in unheated distant tumor portions similar to the abscopal effect described as a response to local radiotherapy [11]
Summary
There is increasing interest in local tumor ablative treatment modalities that can induce immunogenic cell death leading to the generation of tumor-specific immune responses.Hyperthermia in tumor tissues induced by superparamagnetic iron oxide nanoparticles (SPIONs) subjected to an alternating magnetic field (AMF) has been evaluated by various ex-vivo and in-vivo experiments including assessments of biocompatibility, depot stability, and preclinical efficacy [1–7]. Further investigation demonstrated that heat shock proteins (HSPs), including HSP70, trigger potent antitumor immunity during magnetic hyperthermia by the release of HSP-peptide complexes from dying tumor cells which were able to stimulate professional antigen-presenting cells (APCs) such as dendritic cells This in turn leads to the induction of antigen-specific CD4+ and CD8+ T-cell responses [9, 12]. Conclusion Intracavitary thermotherapy combined with radiotherapy can induce a prominent inflammatory reaction around the resection cavity which might trigger potent antitumor immune responses possibly leading to long-term stabilization of recurrent GBM patients. These results warrant further investigations in a prospective phase-I trial
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