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

• Published in: Clinical cancer research 2015-03, Vol.21 (5), p.1151-1160
• Main Authors: Zegers, Catharina M L, Rekers, Nicolle H, Quaden, Dana H F, Lieuwes, Natasja G, Yaromina, Ala, Germeraad, Wilfred T V, Wieten, Lotte, Biessen, Erik A L, Boon, Louis, Neri, Dario, Troost, Esther G C, Dubois, Ludwig J, Lambin, Philippe
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-2676

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. 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. 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. 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.