title: The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40.
abstract: BACKGROUND
  Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma.
  
  
  METHODS
  Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined.
  
  
  RESULTS
  The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a CD8 T cell dependent manner, and promoted tumor regression in 25% of animals with establishment of immunological memory. This response was associated with an increase in ICOS+ CD8 T cells and tumor-specific CTL activity in tumor draining lymph nodes along with an increase in ICOS+ CD8 T cells in responding tumours.
  
  
  CONCLUSIONS
  We show that the post-surgical environment can be significantly altered by the co-administration of adjuvant IMQ and anti-CD40, resulting in strong, systemic anti-tumor activity. Both adjuvants are available for clinical use/trial, hence this treatment regimen has clear translational potential.
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Cleaver
authors.forename: Muhammad
authors.initials: M
authors.lastname: Fahmi Alatas
authors.forename: Ben C
authors.initials: BC
authors.lastname: Wylie
authors.forename: Theresa
authors.initials: T
authors.lastname: Connor
authors.forename: Scott A
authors.initials: SA
authors.lastname: Fisher
authors.forename: Steve
authors.initials: S
authors.lastname: Broomfield
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Lesterhuis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Currie
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Perth, Perth, Western Australia. bruce.robinson@uwa.edu.au.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Robinson
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000634:Aminoquinolines / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D065426:Cytoreduction Surgical Procedures; D004334:Drug Administration Schedule; D005260:Female; D000077271:Imiquimod; D007167:Immunotherapy / Q000379:methods; D008562:Membrane Glycoproteins / Q000819:agonists; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental; D051199:Toll-Like Receptor 7 / Q000819:agonists; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000077271:Imiquimod