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. 2005 Aug 19;94(3):308–313. doi: 10.1111/j.1349-7006.2003.tb01438.x

Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma

Akira Ito 1, Kouji Tanaka 1, Kazuyoshi Kondo 1, Masashige Shinkai 1,4, Hiroyuki Honda 1, Kazuhiko Matsumoto 2, Toshiaki Saida 2, Takeshi Kobayashi 1,✉
PMCID: PMC11160160  PMID: 12824927

Abstract

Immunotherapy (IT) has become an accepted therapeutic modality. We previously reported that intracellular hyperthermia (IH) using magnetic nanoparticles induces antitumor immunity. We undertook these studies in order to study the combined effects of IT and IH on melanoma. Magnetite cationic liposomes (MCLs) have a positive surface charge and generate heat in an alternating magnetic field (AMF) due to hysteresis loss. MCLs were injected into a B16 melanoma nodule in C57BL/6 mice, which were subjected to AMF for 30 min. The temperature at the tumor reached 43°C and was maintained by controlling the magnetic field intensity. At 24 h after IH, interleukin‐2 (IL‐2) or granulocyte macrophage‐colony stimulating factor (GM‐CSF) was injected directly into the melanoma. Mice were divided into six groups: group I (control), group II (IH), group III (IL‐2), group IV (GM‐CSF), group V (IH+IL‐2), and group VI (IH+GM‐CSF). Complete regression of tumors was observed in mice of groups V and VI (75% (6/ 8) and 40% (4/10) of the mice, respectively), while no tumor regression was observed in mice of the other groups. This study supports the combined use of IT and IH using MCLs in patients with advanced malignancies. (Cancer Sci 2003; 94: 308–313)

References

  • 1. Van der Zee J. Heating the patient: a promising approach? Annu Oncol 2002; 13: 1173–84. [DOI] [PubMed] [Google Scholar]
  • 2. Abe M, Hiraoka M, Takahashi M, Egawa S, Matsuda C, Onoyama Y, Morita K, Kakehi M, Sugahara T. Multi‐institutional studies on hyperthermia using an 8‐MHz radiofrequency capacitive heating device (Thermotron RF‐8) in combination with radiation for cancer therapy. Cancer 1986; 58: 1589–95. [DOI] [PubMed] [Google Scholar]
  • 3. Jordan A, Wust P, Fahling H, John W, Hinz A, Felix R. Inductive heating of ferrimagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. Int J Hyperthermia 1993; 9: 51–68. [DOI] [PubMed] [Google Scholar]
  • 4. Minamimura T, Sato H, Kasaoka S, Saito T, Ishizawa S, Takemori S, Tazawa K, Tsukada K. Tumor regression by inductive hyperthermia combined with hepatic embolization using dextran magnetite‐incorporated microspheres in rats. Int J Oncol 2000; 16: 1153–8. [DOI] [PubMed] [Google Scholar]
  • 5. Shinkai M, Matsui M, Kobayashi T. Heat properties of magnetoliposomes for local hyperthermia. Jpn J Hyperthermic Oncol 1994; 10: 168–77. [Google Scholar]
  • 6. Shinkai M, Yanase M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: in vitro study. Jpn J Cancer Res 1996; 87: 1179–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study. Jpn J Cancer Res 1997; 88: 630–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Intracellular hyperthermia for cancer using magnetite cationic liposomes: an in vivo study. Jpn J Cancer Res 1998; 89: 463–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn J Cancer Res 1998; 89: 775–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Burdon RH, Slater A, McMahon M, Cato AC. Hyperthermia and the heat‐shock proteins of HeLa cells. Br J Cancer 1982; 45: 953–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Sciandra JJ, Subjeck JR. Heat shock proteins and protection of proliferation and translation in mammalian cells. Cancer Res 1984; 44: 5188–94. [PubMed] [Google Scholar]
  • 12. Srivastava PK, Menoret A, Basu S, Binder R, Quade K. Heat shock proteins come of age: primitive functions acquired new roles in an adaptive world. Immunity 1998; 8: 657–65. [DOI] [PubMed] [Google Scholar]
  • 13. Menoret A, Chandawarkar R. Heat‐shock protein‐based anticancer immunotherapy: an idea whose time has come. Semin Immunol 1998; 25: 654–60. [PubMed] [Google Scholar]
  • 14. Castelli C, Ciupitu AM, Rini F, Rivoltini L, Mazzocchi A, Kiessling R, Parmiani G. Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells. Cancer Res 2001; 61: 222–7. [PubMed] [Google Scholar]
  • 15. Ito A, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T. Augmentation of MHC class I antigen presentation via heat shock protein expression by hyperthermia. Cancer Immunol Immunother 2001; 50: 515–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Ito A, Shinkai M, Honda H, Yoshikawa K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T. Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immunother 2003; 52: 80–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Farrar WL, Johnson HM, Farrar JJ. Regulation of the production of immune interferon and cytotoxic T lymphocytes by interleukin 2. J Immunol 1981; 126: 1120–5. [PubMed] [Google Scholar]
  • 18. Rosenberg SA, Grimm EA, McGrogan M, Doyle M, Kawasaki E, Koths K, Mark DF. Biological activity of recombinant human interleukin‐2 produced in Escherichia coli . Science 1984; 223: 1412–4. [DOI] [PubMed] [Google Scholar]
  • 19. Hadden JW. Recent advances in the preclinical and clinical immunopharmacology of interleukin‐2: emphasis on IL‐2 as an immunorestorative agent. Cancer Detect Prev 1988; 12: 537–52. [PubMed] [Google Scholar]
  • 20. Gasson JC, Weisbart RH, Kaufman SE, Clark SC, Hewick RM, Wong GG, Golde DW. Purified human granulocyte‐macrophage colony‐stimulating factor: direct action on neutrophils. Science 1984; 226: 1339–42. [DOI] [PubMed] [Google Scholar]
  • 21. Horiguchi J, Warren MK, Kufe D. Expression of the macrophage‐specific colony‐stimulating factor in human monocytes treated with granulocyte‐macrophage colony‐stimulating factor. Blood 1987; 69: 1259–61. [PubMed] [Google Scholar]
  • 22. Burgess AW, Metcalf D. The nature and action of granulocyte‐macrophage colony stimulating factors. Blood 1980; 56: 947–58. [PubMed] [Google Scholar]
  • 23. Brandt SJ, Peters WP, Atwater SK, Kurtzberg J, Borowitz MJ, Jones RB, Shpall EJ, Bast RC Jr, Gilbert CJ, Oette DH. Effect of recombinant human granulocyte‐macrophage colony‐stimulating factor on hematopoietic reconstitution after high‐dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 1988; 318: 869–76. [DOI] [PubMed] [Google Scholar]
  • 24. Vadhan‐Raj S, Keating M, LeMaistre A, Hittelman WN, McCredie K, Trujillo JM, Broxmeyer HE, Henney C, Gutterman JU. Effects of recombinant human granulocyte‐macrophage colony‐stimulating factor in patients with myelodysplastic syndromes. N Engl J Med 1987; 317: 1545–52. [DOI] [PubMed] [Google Scholar]
  • 25. Groopman JE, Mitsuyasu RT, DeLeo MJ, Oette DH, Golde DW. Effect of recombinant human granulocyte‐macrophage colony‐stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med 1987; 317: 593–8. [DOI] [PubMed] [Google Scholar]
  • 26. Antman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, Oette D, Whitley M, Frei E 3rd, Schnipper LE. Effect of recombinant human granulocyte‐macrophage colony‐stimulating factor on chemotherapy‐induced myelosuppression. N Engl J Med 1988; 319: 593–8. [DOI] [PubMed] [Google Scholar]
  • 27. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9: 271–96. [DOI] [PubMed] [Google Scholar]
  • 28. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte‐macrophage colony‐stimulating factor stimulates potent, specific, and long‐lasting anti‐tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Owen CS, Sykes NL. Magnetic labeling and cell sorting. J Immunol Methods 1984; 73: 41–8. [DOI] [PubMed] [Google Scholar]
  • 30. Flotte TJ, Springer TA, Thorbecke GJ. Dendritic cell and macrophage staining by monoclonal antibodies in tissue sections and epidermal sheets. Am J Pathol 1983; 111: 112–24. [PMC free article] [PubMed] [Google Scholar]
  • 31. Suzuki M, Shinkai M, Honda H, Kobayashi T. Anti‐cancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes. Melanoma Res 2003; in press. [DOI] [PubMed]
  • 32. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1998; 12: 991–1045. [DOI] [PubMed] [Google Scholar]
  • 33. Fuchs EJ, Matzinger P. Is cancer dangerous to the immune system? Semin Immunol 1996; 8: 271–80. [DOI] [PubMed] [Google Scholar]
  • 34. Todryk S, Melcher AA, Hardwick N, Linardakis E, Bateman A, Colombo MP, Stoppacciaro A, Vile RG. Heat shock protein 70 induced during tumor cell killing induces Thl cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J Immunol 1999; 163: 1398–408. [PubMed] [Google Scholar]
  • 35. Speiser DE, Miranda R, Zakarian A, Bachmann MF, Mckall‐Faienza K, Odermatt B, Hanahan D, Zinkernagel RM, Ohashi PS. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy. J Exp Med 1997; 186: 645–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy R. Vaccination of patients with B‐cell lymphoma using autologous antigen‐pulsed dendritic cells. Nat Med 1996; 2: 52–8. [DOI] [PubMed] [Google Scholar]
  • 37. Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein‐chaperoned peptide. Science 1995; 269: 1585–8. [DOI] [PubMed] [Google Scholar]
  • 38. Wells AD, Rai SK, Salvato MS, Band H, Malkovsky M. Hsp72‐mediated augmentation of MHC class I surface expression and endogenous antigen presentation. Int Immunol 1998; 10: 609–17. [DOI] [PubMed] [Google Scholar]
  • 39. Shimizu K, Fields RC, Giedlin M, Mule JJ. Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell‐based tumor vaccines. Proc Natl Acad Sci USA 1999; 96: 2268–73. [DOI] [PMC free article] [PubMed] [Google Scholar]

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