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

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Abstract

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.

Abbreviations

CpG:

CpG oligodeoxynucleotides

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DAMP:

Damage-associated molecular pattern

DPPC:

1,2-Dipalmitoyl-sn-glycero-3-phosphocholine

FBS:

Fetal bovine serum

HBS:

HEPES-buffered saline

HT:

Mild hyperthermia

i.p.:

Intraperitoneal

i.v.:

Intravenous

ICI:

Immune checkpoint inhibition

lyso-SPC:

1-Stearoyl-2-lyso-sn-glycero-3-phosphocholine

Na8SOS:

Sodium sucrose octasulfate

NEAA:

Non-essential amino acid

P/S:

Penicillin and streptomycin

PD-1:

Programmed cell death protein 1

PEG2k-DSPE:

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

RMS:

Rhabdomyosarcoma

TEA8SOS:

Sucrose octasulfate triethylammonium salt

ThermoVRL:

Thermosensitive liposomal vinorelbine

VRL:

Vinorelbine tartrate

References

  1. Crompton JG, Ogura K, Bernthal NM, Kawai A, Eilber FC. Local control of soft tissue and bone sarcomas. J Clin Oncol Wolters Kluwer. 2018;36:111–7.

    Article  CAS  Google Scholar 

  2. Mahvi DA, Liu R, Grinstaff MW, Colson YL, Raut CP. Local cancer recurrence: the realities, challenges, and opportunities for new therapies. CA Cancer J Clin. 2018;68:488–505.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mazzoleni S, Bisogno G, Garaventa A, Cecchetto G, Ferrari A, Sotti G, et al. Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer. 2005;104:183–90.

    Article  PubMed  Google Scholar 

  4. Rhabdomyosarcoma - Childhood - Statistics [Internet]. Cancer.Net. 2012 [cited 2022 Jun 22]. Available from: https://www.cancer.net/cancer-types/rhabdomyosarcoma-childhood/statistics.

  5. Okcu MF, John H. Rhabdomyosarcoma in childhood, adolescence, and adulthood: treatment [Internet]. UpToDate. 2022 [cited 2022 Jun 22]. Available from: https://www-uptodate-com.myaccess.library.utoronto.ca/contents/rhabdomyosarcoma-in-childhood-adolescence-and-adulthood-treatment?search=rhabdomyosarcoma%20treatment&source=search_result&selectedTitle=1~109&usage_type=default&display_rank=1#H31.

  6. Franco MS, Gomes ER, Roque MC, Oliveira MC. Triggered drug release from liposomes: exploiting the outer and inner tumor environment. Front Oncol [Internet]. 2021 [cited 2022 Mar 16];11. Available from: https://www.frontiersin.org/article/https://doi.org/10.3389/fonc.2021.623760.

  7. Yatvin MB, Weinstein JN, Dennis WH, Blumenthal R. Design of liposomes for enhanced local Release of drugs by hyperthermia. Science. American Association for the Advancement of Science; 1978;202:1290–3.

  8. Motamarry A, Asemani D, Haemmerich D. Thermosensitive liposomes. Liposomes [Internet]. 2017 [cited 2019 Nov 24]; Available from: https://www.intechopen.com/books/liposomes/thermosensitive-liposomes.

  9. Mannaris C, Efthymiou E, Meyre M-E, Averkiou MA. In vitro localized release of thermosensitive liposomes with ultrasound-induced hyperthermia. Ultrasound Med Biol. 2013;39:2011–20.

    Article  PubMed  Google Scholar 

  10. Viglianti BL, Dewhirst MW, Boruta RJ, Park J-Y, Landon C, Fontanella AN, et al. Systemic anti-tumour effects of local thermally sensitive liposome therapy. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2014;30:385–92.

    Article  CAS  Google Scholar 

  11. Regenold M, Bannigan P, Evans JC, Waspe A, Temple MJ, Allen C. Turning down the heat: the case for mild hyperthermia and thermosensitive liposomes. Nanomedicine Nanotechnol Biol Med. 2022;40: 102484.

    Article  CAS  Google Scholar 

  12. Lyon PC, Gray MD, Mannaris C, Folkes LK, Stratford M, Campo L, et al. Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial. Lancet Oncol. 2018;19:1027–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Maar JS, Suelmann BBM, Braat MNGJA, van Diest PJ, Vaessen HHB, Witkamp AJ, et al. Phase I feasibility study of magnetic resonance guided high intensity focused ultrasound-induced hyperthermia, lyso-thermosensitive liposomal doxorubicin and cyclophosphamide in de novo stage IV breast cancer patients: study protocol of the i-GO study. BMJ Open [Internet]. 2020 [cited 2021 Jan 8];10. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692846/.

  14. Borys N, Dewhirst MW. Drug development of lyso-thermosensitive liposomal doxorubicin: combining hyperthermia and thermosensitive drug delivery. Adv Drug Deliv Rev. 2021;178: 113985.

    Article  CAS  PubMed  Google Scholar 

  15. Dillekås H, Rogers MS, Straume O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019;8:5574–6.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Benzekry S, Tracz A, Mastri M, Corbelli R, Barbolosi D, Ebos JML. Modeling spontaneous metastasis following surgery: an in vivo-in silico approach. Cancer Res. 2016;76:535–47.

    Article  CAS  PubMed  Google Scholar 

  17. Mole RH. Whole Body Irradiation—radiobiology or medicine? Br J Radiol. The British Institute of Radiology. 1953;26:234–41.

    Article  CAS  Google Scholar 

  18. Demaria S, Formenti SC. The abscopal effect 67 years later: from a side story to center stage. Br J Radiol. 2020;93:20200042.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016;40:25–37.

    Article  PubMed  Google Scholar 

  20. Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer Nature Publishing Group. 2018;18:313–22.

    Article  CAS  Google Scholar 

  21. Grass GD, Krishna N, Kim S. The immune mechanisms of abscopal effect in radiation therapy. Curr Probl Cancer. 2016;40:10–24.

    Article  PubMed  Google Scholar 

  22. Xie Q, Li Z, Liu Y, Zhang D, Su M, Niitsu H, et al. Translocator protein-targeted photodynamic therapy for direct and abscopal immunogenic cell death in colorectal cancer. Acta Biomater. 2021;134:716–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Seiwert TY, Kiess AP. Time to Debunk an Urban Myth? The “abscopal effect” with radiation and anti–PD-1. J Clin Oncol Wolters Kluwer. 2021;39:1–3.

    Article  Google Scholar 

  24. Payne M, Bossmann SH, Basel MT. Direct treatment versus indirect: thermo-ablative and mild hyperthermia effects. WIREs Nanomed Nanobiotechnol. 2020;12: e1638.

    Article  PubMed  Google Scholar 

  25. Skitzki JJ, Repasky EA, Evans SS. Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs Lond Engl. 2000;2009(10):550–8.

    Google Scholar 

  26. Minnaar CA, Kotzen JA, Ayeni OA, Vangu MDT, Baeyens A. Potentiation of the abscopal effect by modulated electro-hyperthermia in locally advanced cervical cancer patients. Front Oncol. 2020;10:376.

  27. Oei AL, Korangath P, Mulka K, Helenius M, Coulter JB, Stewart J, et al. Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2019;36:47–63.

    Article  CAS  Google Scholar 

  28. Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z. Immunogenic cell death in cancer therapy: present and emerging inducers. J Cell Mol Med. 2019;23:4854–65.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44:343–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Orecchioni S, Talarico G, Labanca V, Calleri A, Mancuso P, Bertolini F. Vinorelbine, cyclophosphamide and 5-FU effects on the circulating and intratumoural landscape of immune cells improve anti-PD-L1 efficacy in preclinical models of breast cancer and lymphoma. Br J Cancer. 2018;118:1329–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tanaka H, Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic agents based on their differential in vitro impacts on dendritic cells. Cancer Res. 2009;69:6978–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. Nature Publishing Group; 2020;17:725–41.

  33. Lévesque S, Le Naour J, Pietrocola F, Paillet J, Kremer M, Castoldi F, et al. A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology. 2019;8: e1657375.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29:2163–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Regenold M, Steigenberger J, Siniscalchi E, Dunne M, Casettari L, Heerklotz H, et al. Determining critical parameters that influence in vitro performance characteristics of a thermosensitive liposome formulation of vinorelbine. J Controlled Release [Internet]. 2020 [cited 2020 Sep 11]; Available from: http://www.sciencedirect.com/science/article/pii/S0168365920305009.

  36. Aston WJ, Hope DE, Nowak AK, Robinson BW, Lake RA, Lesterhuis WJ. A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice. BMC Cancer. 2017;17:684.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dou YN, Zheng J, Foltz WD, Weersink R, Chaudary N, Jaffray DA, et al. Heat-activated thermosensitive liposomal cisplatin (HTLC) results in effective growth delay of cervical carcinoma in mice. J Controlled Release. 2014;178:69–78.

    Article  CAS  Google Scholar 

  38. Regenold M, Kaneko K, Wang X, Peng HB, Evans JC, Bannigan P, et al. Triggered release from thermosensitive liposomes improves tumor targeting of vinorelbine [Internet]. bioRxiv; 2022 [cited 2022 Nov 3]. p. 2022.11.02.514937. Available from: https://www.biorxiv.org/content/10.1101/2022.11.02.514937v1 .

  39. Banno B, Ickenstein LM, Chiu GNC, Bally MB, Thewalt J, Brief E, et al. The functional roles of poly(ethylene glycol)-lipid and lysolipid in the drug retention and release from lysolipid-containing thermosensitive liposomes in vitro and in vivo. J Pharm Sci. 2010;99:2295–308.

    Article  CAS  PubMed  Google Scholar 

  40. Schmidt R. Neuartige thermosensitive Liposomen zur zielgerichteten Therapie solider Tumoren - Charakterisierung in vitro und in vivo - [Internet] [Text.PhDThesis]. Ludwig-Maximilians-Universität München; 2011 [cited 2019 Apr 3]. Available from: https://edoc.ub.uni-muenchen.de/12735/.

  41. Ickenstein LM. Triggered drug release from thermosensitive liposomes. 289.

  42. Barr JT, Tran TB, Rock BM, Wahlstrom JL, Dahal UP. Strain-dependent variability of early discovery small molecule pharmacokinetics in mice: does strain matter? Drug Metab Dispos. 2020;48:613–21.

    Article  CAS  PubMed  Google Scholar 

  43. Li F, Ulrich ML, Shih VF-S, Cochran JH, Hunter JH, Westendorf L, et al. Mouse strains influence clearance and efficacy of antibody and antibody–drug conjugate via Fc–FcγR interaction. Mol Cancer Ther. 2019;18:780–7.

  44. Czerniak R. Gender-based differences in pharmacokinetics in laboratory animal models. Int J Toxicol. 2001;20:161–3.

    Article  CAS  PubMed  Google Scholar 

  45. Lin Y-Y, Kao H-W, Li J-J, Hwang J-J, Tseng Y-L, Lin W-J, et al. Tumor burden talks in cancer treatment with PEGylated liposomal drugs. PLOS ONE. Public Libr Sci. 2013;8:e63078.

  46. Meadors JL, Cui Y, Chen Q-R, Song YK, Khan J, Merlino G, et al. Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. Pediatr Blood Cancer. 2011;57:921–9.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dou YN, Weersink RA, Foltz WD, Zheng J, Chaudary N, Jaffray DA, et al. Custom-designed laser-based heating apparatus for triggered release of cisplatin from thermosensitive liposomes with magnetic resonance image guidance. J Vis Exp JoVE [Internet]. 2015 [cited 2020 Jan 18]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694025/.

  48. van Rhoon GC, Franckena M, ten Hagen TLM. A moderate thermal dose is sufficient for effective free and TSL based thermochemotherapy. Adv Drug Deliv Rev [Internet]. 2020 [cited 2020 Jul 30]; Available from: http://www.sciencedirect.com/science/article/pii/S0169409X2030020X.

  49. van Rhoon GC. Is CEM43 still a relevant thermal dose parameter for hyperthermia treatment monitoring? Int J Hyperthermia Taylor & Francis. 2016;32:50–62.

    Article  Google Scholar 

  50. Drummond DC, Noble CO, Guo Z, Hayes ME, Park JW, Ou C-J, et al. Improved pharmacokinetics and efficacy of a highly stable nanoliposomal vinorelbine. J Pharmacol Exp Ther. 2009;328:321–30.

    Article  CAS  PubMed  Google Scholar 

  51. Dunne MR. The effect of hyperthermia on nanomedicine efficacy [Internet] [Thesis]. 2020 [cited 2022 Oct 16]. Available from: https://tspace.library.utoronto.ca/handle/1807/105824.

  52. Dunne M, Epp-Ducharme B, Sofias AM, Regenold M, Dubins DN, Allen C. Heat-activated drug delivery increases tumor accumulation of synergistic chemotherapies. J Controlled Release [Internet]. 2019 [cited 2019 Jul 9]; Available from: http://www.sciencedirect.com/science/article/pii/S0168365919303220.

  53. Kheirolomoom A, Lai C-Y, Tam SM, Mahakian LM, Ingham ES, Watson KD, et al. Complete regression of local cancer using temperature-sensitive liposomes combined with ultrasound-mediated hyperthermia. J Controlled Release. 2013;172:266–73.

    Article  CAS  Google Scholar 

  54. Dou YN, Dunne M, Huang H, Mckee T, Chang MC, Jaffray DA, et al. Thermosensitive liposomal cisplatin in combination with local hyperthermia results in tumor growth delay and changes in tumor microenvironment in xenograft models of lung carcinoma. J Drug Target. 2016;24:865–77.

    Article  CAS  PubMed  Google Scholar 

  55. Needham D, Anyarambhatla G, Kong G, Dewhirst MW. A New Temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res. 2000;60:1197–201.

    CAS  PubMed  Google Scholar 

  56. Bing C, Patel P, Staruch RM, Shaikh S, Nofiele J, Wodzak Staruch M, et al. Longer heating duration increases localized doxorubicin deposition and therapeutic index in Vx2 tumors using MR-HIFU mild hyperthermia and thermosensitive liposomal doxorubicin. Int J Hyperthermia. Taylor & Francis. 2019;36:195–202.

    Article  CAS  Google Scholar 

  57. Gasselhuber A, Dreher MR, Negussie A, Wood BJ, Rattay F, Haemmerich D. Mathematical spatio-temporal model of drug delivery from low temperature sensitive liposomes during radiofrequency tumour ablation. Int J Hyperthermia Taylor & Francis. 2010;26:499–513.

    Article  CAS  Google Scholar 

  58. Ranjan A, Jacobs G, Woods DL, Negussie AH, Partanen A, Yarmolenko PS, et al. Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. J Controlled Release. 2012;158:487–94.

    Article  CAS  Google Scholar 

  59. Kok HP, Cressman ENK, Ceelen W, Brace CL, Ivkov R, Grüll H, et al. Heating technology for malignant tumors: a review. Int J Hyperthermia. 2020;37:711–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Santos MA, Wu S-K, Regenold M, Allen C, Goertz DE, Hynynen K. Novel fractionated ultrashort thermal exposures with MRI-guided focused ultrasound for treating tumors with thermosensitive drugs. Sci Adv. American Association for the Advancement of Science; 2020;6:eaba5684.

  61. Crezee J, Zweije R, Sijbrands J, Kok HP. Dedicated 70 MHz RF systems for hyperthermia of challenging tumor locations. Int J Microw Wirel Technol. Cambridge University Press; 2020;12:839–47.

  62. World Health Organization. Cancer-WHO [Internet]. World Health Organ. 2022 [cited 2022 May 17]. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer.

  63. Zhou J, Lu X, Chang W, Wan C, Lu X, Zhang C, et al. PLUS: Predicting cancer metastasis potential based on positive and unlabeled learning. PLOS Comput Biol. Public Libr Sci. 2022;18:e1009956.

  64. Untargeted large volume hyperthermia reduces tumor drug uptake from thermosensitive liposomes. IEEE Open J Eng Med Biol. 2021;2:187–97.

  65. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. Nature Publishing Group; 2020;5:1–17.

  66. Nakahata K, Simons BW, Pozzo E, Shuck R, Kurenbekova L, Prudowsky Z, et al. K-Ras and p53 mouse model with molecular characteristics of human rhabdomyosarcoma and translational applications. Dis Model Mech. 2022;15:dmm049004.

  67. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. American Association for the Advancement of Science; 2014;6:237ra67–237ra67.

  68. Guerin MV, Finisguerra V, Van den Eynde BJ, Bercovici N, Trautmann A. Preclinical murine tumor models: a structural and functional perspective. Settleman J, Kawakami Y, editors. eLife. eLife Sciences Publications, Ltd; 2020;9:e50740.

  69. Zhang W, Fan W, Rachagani S, Zhou Z, Lele SM, Batra SK, et al. Comparative study of subcutaneous and orthotopic mouse models of prostate cancer: vascular perfusion, vasculature density, hypoxic burden and BB2r-targeting efficacy. Sci Rep. Nature Publishing Group; 2019;9:11117.

  70. Brand M, Laban S, Theodoraki M-N, Doescher J, Hoffmann TK, Schuler PJ, et al. Characterization and differentiation of the tumor microenvironment (TME) of orthotopic and subcutaneously grown head and neck squamous cell carcinoma (HNSCC) in immunocompetent mice. Int J Mol Sci. 2020;22:247.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kheirolomoom A, Ingham ES, Mahakian LM, Tam SM, Silvestrini MT, Tumbale SK, et al. CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery. J Control Release Off J Control Release Soc. 2015;220:253–64.

    Article  CAS  Google Scholar 

  72. Kheirolomoom A, Silvestrini MT, Ingham ES, Mahakian LM, Tam SM, Tumbale SK, et al. Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. J Controlled Release. 2019;303:42–54.

    Article  CAS  Google Scholar 

  73. Frey B, Weiss E-M, Rubner Y, Wunderlich R, Ott OJ, Sauer R, et al. Old and new facts about hyperthermia-induced modulations of the immune system. Int J Hyperthermia. 2012;28:528–42.

    Article  CAS  PubMed  Google Scholar 

  74. Dunne M, Regenold M, Allen C. Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy. Adv Drug Deliv Rev [Internet]. 2020 [cited 2020 Jul 27]; Available from: http://www.sciencedirect.com/science/article/pii/S0169409X20300831.

  75. Issels RD, Lindner LH, von Bergwelt-Baildon M, Lang P, Rischpler C, Diem H, et al. Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma – a case report. Int J Hyperthermia. Taylor & Francis. 2020;37:55–65.

    Article  CAS  Google Scholar 

  76. Ibuki Y, Takahashi Y, Tamari K, Minami K, Seo Y, Isohashi F, et al. Local hyperthermia combined with CTLA-4 blockade induces both local and abscopal effects in a murine breast cancer model. Int J Hyperthermia. Taylor & Francis. 2021;38:363–71.

    Article  CAS  Google Scholar 

  77. Baklaushev VP, Kilpeläinen A, Petkov S, Abakumov MA, Grinenko NF, Yusubalieva GM, et al. Luciferase expression allows bioluminescence imaging but imposes limitations on the orthotopic mouse (4T1) model of breast cancer. Sci Rep. 2017;7:7715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Varna M, Bertheau P, Legrès LG. Tumor microenvironment in human tumor xenografted mouse models. J Anal Oncol [Internet]. 2014 [cited 2022 Jul 5];3. Available from: https://neoplasiaresearch.com/pms/index.php/jao/article/view/226.

  79. Beachy SH, Repasky EA. Toward establishment of temperature thresholds for immunological impact of heat exposure in humans. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2011;27:344–52.

    Article  Google Scholar 

  80. Baronzio GF, Seta RD, D’Amico M, Baronzio A, Freitas I, Forzenigo G, et al. Effects of local and whole body hyperthermia on immunity [Internet]. Madame Curie Biosci. Database Internet. Landes Bioscience; 2013 [cited 2022 Jun 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK6083/.

  81. Kim SI, Cassella CR, Byrne KT. Tumor burden and immunotherapy: impact on immune infiltration and therapeutic outcomes. Front Immunol [Internet]. 2021 [cited 2022 Jul 5];11. Available from: https://www.frontiersin.org/articles/https://doi.org/10.3389/fimmu.2020.629722.

  82. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. Nature Publishing Group. 2021;21:345–59.

    Article  CAS  Google Scholar 

  83. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28:690–714.

    Article  CAS  PubMed  Google Scholar 

  84. Lin RA, Lin JK, Lin S-Y. Mechanisms of immunogenic cell death and immune checkpoint blockade therapy. Kaohsiung J Med Sci. 2021;37:448–58.

    Article  CAS  PubMed  Google Scholar 

  85. Bezu L, Sauvat A, Humeau J, Gomes-da-Silva LC, Iribarren K, Forveille S, et al. eIF2α phosphorylation is pathognomonic for immunogenic cell death. Cell Death Differ. Nature Publishing Group. 2018;25:1375–93.

    Article  CAS  Google Scholar 

  86. Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C, et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. OncoImmunology. Taylor & Francis; 2013;2:e27025.

  87. Wen C-C, Chen H-M, Chen S-S, Huang L-T, Chang W-T, Wei W-C, et al. Specific microtubule-depolymerizing agents augment efficacy of dendritic cell-based cancer vaccines. J Biomed Sci. 2011;18:44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yu Q, Tang X, Zhao W, Qiu Y, He J, Wan D, et al. Mild hyperthermia promotes immune checkpoint blockade-based immunotherapy against metastatic pancreatic cancer using size-adjustable nanoparticles. Acta Biomater. 2021;133:244–56.

    Article  CAS  PubMed  Google Scholar 

  89. Hurwitz MD. Hyperthermia and immunotherapy: clinical opportunities. Int J Hyperthermia. Taylor & Francis. 2019;36:4–9.

    Article  CAS  Google Scholar 

  90. Altinoz MA, Ozpinar A, Alturfan EE, Elmaci I. Vinorelbine’s anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: hypotheses with implications for chemo-immunotherapy of advanced cancers and pediatric gliomas. J Chemother. Taylor & Francis. 2018;30:203–12.

    CAS  Google Scholar 

  91. Moskowitz AJ, Shah G, Schöder H, Ganesan N, Drill E, Hancock H, et al. Phase II trial of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin as second-line therapy for relapsed or refractory classical Hodgkin lymphoma. J Clin Oncol Wolters Kluwer. 2021;39:3109–17.

    Article  CAS  Google Scholar 

  92. D’Ascanio M, Pezzuto A, Fiorentino C, Sposato B, Bruno P, Grieco A, et al. Metronomic chemotherapy with vinorelbine produces clinical benefit and low toxicity in frail elderly patients affected by advanced non-small cell lung cancer. BioMed Res Int. Hindawi; 2018;2018:e6278403.

  93. Vergnenegre A, Monnet I, Bizieux A, Bernardi M, Chiapa AM, Léna H, et al. Open-label Phase II trial to evaluate safety and efficacy of second-line metronomic oral vinorelbine–atezolizumab combination for stage-IV non-small-cell lung cancer – VinMetAtezo trial, (GFPC‡ 04–2017). Future Oncol Future Medicine. 2020;16:5–10.

    Article  CAS  Google Scholar 

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Acknowledgements

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).

Funding

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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All animal studies were conducted in accordance with the guidelines of the Animal Care Committee of the University Health Network (UHN, Toronto, ON, Canada).

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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). https://doi.org/10.1007/s13346-022-01272-w

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