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Harnessing immunotherapy to enhance the systemic anti-tumor effects of thermosensitive liposomes

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Chemotherapy plays an important role in debulking tumors in advance of surgery and/or radiotherapy, tackling residual disease, and treating metastatic disease. In recent years many promising advanced drug delivery strategies have emerged that offer more targeted delivery approaches to chemotherapy treatment. For example, thermosensitive liposome-mediated drug delivery in combination with localized mild hyperthermia can increase local drug concentrations resulting in a reduction in systemic toxicity and an improvement in local disease control. However, the majority of solid tumor-associated deaths are due to metastatic spread. A therapeutic approach focused on a localized target area harbors the risk of overlooking and undertreating potential metastatic spread. Previous studies reported systemic, albeit limited, anti-tumor effects following treatment with thermosensitive liposomal chemotherapy and localized mild hyperthermia. This work explores the systemic treatment capabilities of a thermosensitive liposome formulation of the vinca alkaloid vinorelbine in combination with mild hyperthermia in an immunocompetent murine model of rhabdomyosarcoma. This treatment approach was found to be highly effective at heated, primary tumor sites. However, it demonstrated limited anti-tumor effects in secondary, distant tumors. As a result, the addition of immune checkpoint inhibition therapy was pursued to further enhance the systemic anti-tumor effect of this treatment approach. Once combined with immune checkpoint inhibition therapy, a significant improvement in systemic treatment capability was achieved. We believe this is one of the first studies to demonstrate that a triple combination of thermosensitive liposomes, localized mild hyperthermia, and immune checkpoint inhibition therapy can enhance the systemic treatment capabilities of thermosensitive liposomes.

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Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.



CpG oligodeoxynucleotides


Cytotoxic T-lymphocyte-associated protein 4


Damage-associated molecular pattern




Fetal bovine serum


HEPES-buffered saline


Mild hyperthermia






Immune checkpoint inhibition




Sodium sucrose octasulfate


Non-essential amino acid


Penicillin and streptomycin


Programmed cell death protein 1


N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine




Sucrose octasulfate triethylammonium salt


Thermosensitive liposomal vinorelbine


Vinorelbine tartrate


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These studies were supported by a CIHR project grant to C.A. MR holds a Centre for Pharmaceutical Oncology (CPO) scholarship. The authors acknowledge the use of equipment in the CPO at the University of Toronto as well as the STTARR Innovation Centre (University Health Network).


These studies were supported by a CIHR project grant to C.A (Grant Number 504264).

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Maximilian Regenold: conceptualization, methodology, investigation, formal analysis, writing—original draft, writing—review editing, and visualization. Xuehan Wang: investigation, writing—review and editing. Kan Kaneko: investigation, writing—review and editing. Pauric Bannigan: writing—original draft, writing—review and editing. Christine Allen: conceptualization, writing—review and editing, supervision, funding acquisition.

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Correspondence to Christine Allen.

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Regenold, M., Wang, X., Kaneko, K. et al. Harnessing immunotherapy to enhance the systemic anti-tumor effects of thermosensitive liposomes. Drug Deliv. and Transl. Res. 13, 1059–1073 (2023).

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