title: Radiotherapy combined with the immunocytokine L19-IL2 provides long-lasting antitumor effects.
abstract: OBJECTIVE
  Radiotherapy modifies the tumor microenvironment and causes the release of tumor antigens, which can enhance the effect of immunotherapy. L19 targets the extra domain B (ED-B) of fibronectin, a marker for tumor neoangiogenesis, and can be used as immunocytokine when coupled to IL2. We hypothesize that radiotherapy in combination with L19-IL2 provides an enhanced antitumor effect, which is dependent on ED-B expression.
  
  
  METHODS
  Mice were injected with syngeneic C51 colon carcinoma, Lewis lung carcinoma (LLC), or 4T1 mammary carcinoma cells. Tumor growth delay, underlying immunologic parameters, and treatment toxicity were evaluated after single-dose local tumor irradiation and systemic administration of L19-IL2 or equimolar controls.
  
  
  RESULTS
  ED-B expression was high, intermediate, and low for C51, LLC, and 4T1, respectively. The combination therapy showed (i) a long-lasting synergistic effect for the C51 model with 75% of tumors being cured, (ii) an additive effect for the LLC model, and (iii) no effect for the 4T1 model. The combination treatment resulted in a significantly increased cytotoxic (CD8(+)) T-cell population for both C51 and LLC. Depletion of CD8(+) T cells abolished the benefit of the combination therapy.
  
  
  CONCLUSIONS
  These data provide the first evidence for an increased therapeutic potential by combining radiotherapy with L19-IL2 in ED-B-positive tumors. This new opportunity in cancer treatment will be investigated in a phase I clinical study for patients with an oligometastatic solid tumor (NCT02086721). An animation summarizing our results is available at https://www.youtube.com/watch?v=xHbwQuCTkRc.
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands. karen.zegers@maastro.nl.
authors.forename: Catharina M L
authors.initials: CM
authors.lastname: Zegers
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Nicolle H
authors.initials: NH
authors.lastname: Rekers
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands. Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Dana H F
authors.initials: DH
authors.lastname: Quaden
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Natasja G
authors.initials: NG
authors.lastname: Lieuwes
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Ala
authors.initials: A
authors.lastname: Yaromina
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Wilfred T V
authors.initials: WT
authors.lastname: Germeraad
authors.affiliation: Department of Transplantation Immunology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Wieten
authors.affiliation: Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Bioceros, Utrecht, the Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Esther G C
authors.initials: EG
authors.lastname: Troost
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Ludwig J
authors.initials: LJ
authors.lastname: Dubois
authors.affiliation: Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008212:Lymphocyte Depletion; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D011879:Radiotherapy Dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005353:Fibronectins; C554817:L19-IL2 immunocytokine; D011993:Recombinant Fusion Proteins