title: Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.
abstract: OBJECTIVE
  This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody.
  
  
  METHODS
  TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy x 1, 8 Gy x 3, or 6 Gy x 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model.
  
  
  RESULTS
  In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-gamma production was proportional to the inhibition of the secondary tumor.
  
  
  CONCLUSIONS
  Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti-CTLA-4 antibody in two preclinical carcinoma models.
authors.affiliation: Department of Pathology, New York University School of Medicine and New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: M Zahidunnabi
authors.initials: MZ
authors.lastname: Dewan
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Galloway
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawashima
authors.forename: J Keith
authors.initials: JK
authors.lastname: Dewyngaert
authors.forename: James S
authors.initials: JS
authors.lastname: Babb
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Formenti
authors.forename: Sandra
authors.initials: S
authors.lastname: Demaria
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002277:Carcinoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011879:Radiotherapy Dosage
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007371:Interferon-gamma
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