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Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody

2009· article· en· 1 648 citations· W2117878645 sur OpenAlex· 10.1158/1078-0432.ccr-09-0265

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Résumé

PURPOSE: This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody. EXPERIMENTAL DESIGN: 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.

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La notice

Revue
Clinical Cancer Research
Thématique
Cancer Immunotherapy and Biomarkers
Domaine
Medicine
Établissements canadiens
Organismes subventionnaires
National Cancer InstituteNational Institutes of HealthYork UniversityChemotherapy FoundationBreast Cancer Research FoundationU.S. Department of Defense
Mots-clés
Abscopal effectRadiation therapyMedicineCD8Cancer researchAntibodyImmunotherapyGrowth inhibitionNasopharyngeal carcinomaCarcinomaDose fractionationRegimenImmune systemOncologyInternal medicineImmunologyCell growthBiology
Résumé présent dans OpenAlex
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