title: Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.
abstract: Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.
authors.affiliation: Cork Cancer Research Centre, Mercy University Hospital and Leslie C Quick Jnr Laboratory, University College Cork, Cork, Ireland.
authors.forename: M C
authors.initials: MC
authors.lastname: Whelan
authors.forename: G
authors.initials: G
authors.lastname: Casey
authors.forename: M
authors.initials: M
authors.lastname: MacConmara
authors.forename: J A
authors.initials: JA
authors.lastname: Lederer
authors.forename: D
authors.initials: D
authors.lastname: Soden
authors.forename: J K
authors.initials: JK
authors.lastname: Collins
authors.forename: M
authors.initials: M
authors.lastname: Tangney
authors.forename: G C
authors.initials: GC
authors.lastname: O'Sullivan
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D018122:B7-1 Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D055261:Immunogenetic Phenomena; D007167:Immunotherapy / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor