title: Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70.
abstract: Chaperone Hsp70 can activate adaptive immunity suggesting its possible application as an antitumor vaccine. To assess the therapeutic capacity of Hsp70 we administered purified chaperone into a C6 glioblastoma brain tumor and explored the viability and tumor size as well as interferon gamma (IFNγ) production and cytotoxicity of lymphocytes in the treated animals. Targeted intratumoral injection of Hsp70 resulted in its distribution within the area of glioblastoma, and caused significant inhibition of tumor progression as confirmed by magnetic resonance imaging. The delay in tumor growth corresponded to the prolonged survival of tumor-bearing animals of up to 31 days versus 20 days in control. Continuous administration of Hsp70 with an osmotic pump increased survival even further (39 days). Therapeutic efficacy was associated with infiltration to glioblastoma of NK cells (Ly-6c+) and T lymphocytes (CD3+, CD4+ and CD8+) as well as with an increase in the activity of NK cells (granzyme B production) and CD8+ T lymphocytes as shown by IFNγ ELISPOT assay. Furthermore, we found that Hsp70 treatment caused concomitantly, with a tenfold elevated IFNγ production, an increase in anti-C6 tumor cytotoxicity of lymphocytes. In conclusion, continuous intratumoral delivery of Hsp70 demonstrates high therapeutic potential and therefore could be applied in the treatment of glioblastoma.
authors.affiliation: Laboratory of Cell Protection Mechanisms, Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg, Russia.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Shevtsov
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Pozdnyakov
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Mikhrina
authors.forename: Ludmila Y
authors.initials: LY
authors.lastname: Yakovleva
authors.forename: Boris P
authors.initials: BP
authors.lastname: Nikolaev
authors.forename: Anatolii V
authors.initials: AV
authors.lastname: Dobrodumov
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Komarova
authors.forename: Darya A
authors.initials: DA
authors.lastname: Meshalkina
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Ischenko
authors.forename: Emil
authors.initials: E
authors.lastname: Pitkin
authors.forename: Irina V
authors.initials: IV
authors.lastname: Guzhova
authors.forename: Boris A
authors.initials: BA
authors.lastname: Margulis
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D049109:Cell Proliferation; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051381:Rats; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D007371:Interferon-gamma
keywords: antitumor immunity; brain tumor; glioblastoma; heat shock protein 70; immunotherapy