title: In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments.
abstract: Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929-41. ©2016 AACR.
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin. zmorris@uwhealth.org.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Morris
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Guy
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: David M
authors.initials: DM
authors.lastname: Francis
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Gressett
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Lauryn R
authors.initials: LR
authors.lastname: Werner
authors.affiliation: Department of Biostatistics and Bioinformatics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Lakeesha L
authors.initials: LL
authors.lastname: Carmichael
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Yang
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Armstrong
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Shyhmin
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Oncology, St. Jude Children's Hospital, Memphis, Tennessee.
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.affiliation: Provenance Biopharmaceuticals, Carlisle, Massachusetts.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.affiliation: Bristol Myers Squibb, Redwood, California.
authors.forename: Alan
authors.initials: A
authors.lastname: Korman
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Hank
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin. Department of Pediatrics, University of Wisconsin, Madison, Wisconsin. Department of Genetics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D060908:CTLA-4 Antigen / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007376:Interleukin-2 / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D014611:Vaccination; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007376:Interleukin-2