Radiotherapy combined with the immunocytokine L19-IL2 provides long-lasting antitumor effects

Clin Cancer Res. 2015 Mar 1;21(5):1151-60. doi: 10.1158/1078-0432.CCR-14-2676. Epub 2014 Dec 31.


Purpose: 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.

Experimental design: 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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Disease Models, Animal
  • Fibronectins / metabolism
  • Humans
  • Lymphocyte Depletion
  • Mice
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Neoplasms / pathology*
  • Neoplasms / radiotherapy
  • Radiotherapy Dosage
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / pharmacology*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tumor Burden / drug effects
  • Tumor Burden / radiation effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Fibronectins
  • L19-IL2 immunocytokine
  • Recombinant Fusion Proteins