title: Quantitative CD3 PET Imaging Predicts Tumor Growth Response to Anti-CTLA-4 Therapy.
abstract: Immune checkpoint inhibitors have made rapid advances, resulting in multiple Food and Drug Administration-approved therapeutics that have markedly improved survival. However, these benefits are limited to a minority subpopulation that achieves a response. Predicting which patients are most likely to benefit would be valuable for individual therapy optimization. T-cell markers such as CD3-by examining active recruitment of the T cells responsible for cancer-cell death-represent a more direct approach to monitoring tumor immune response than pretreatment biopsy or genetic screening. This approach could be especially effective as numerous different therapeutic strategies emerge, decreasing the need for drug-specific biomarkers and instead focusing on T-cell infiltration, which has been previously correlated with treatment response.
  
  
  METHODS
  A CD3 PET imaging agent targeting T cells was synthesized to test the role of such imaging as a predictive marker. The89Zr-p-isothiocyanatobenzyl-deferoxamine-CD3 PET probe was assessed in a murine tumor xenograft model of anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy of colon cancer.
  
  
  RESULTS
  Imaging on day 14 revealed 2 distinct groups of mice stratified by PET signal intensity. Although there was no significant difference in tumor volume on the day of imaging, in the high-uptake group subsequent measurements revealed significantly smaller tumors than in either the low-uptake group or the untreated controls. In contrast, there was no significant difference in the size of tumors between the low-uptake and untreated control mice.
  
  
  CONCLUSIONS
  These findings indicate that high CD3 PET uptake in the anti-CTLA-4-treated mice correlated with subsequent reduced tumor volume and was a predictive biomarker of response.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Larimer
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Wehrenberg-Klee
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alexander
authors.initials: A
authors.lastname: Caraballo
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts umahmood@mgh.harvard.edu.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology / Q000628:therapy; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D060908:CTLA-4 Antigen
keywords: CD3; PET; cancer immunotherapy; response prediction