Cancer Therapy: Preclinical RadiotherapyCombinedwith the Immunocytokine L19-IL2 Provides Long-lasting Antitumor Effects

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 singledose local tumor irradiation and systemic administration of L19IL2 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 (CD8þ) T-cell population for both C51 and LLC. Depletion of CD8þ 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 treatmentwill 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.ClinCancer Res; 21(5); 1151–60. 2014