title: The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF.
abstract: Systemic high-dose IL2 promotes long-term survival in a subset of metastatic melanoma patients, but this treatment is accompanied by severe toxicities. The immunocytokine L19-IL2, in which IL2 is fused to the human L19 antibody capable of selective accumulation on tumor neovasculature, has recently shown encouraging clinical activity in patients with metastatic melanoma. In this study, we have investigated the therapeutic performance of L19-IL2, administered systemically in combination with a murine anti-CTLA-4 antibody or with a second clinical-stage immunocytokine (L19-TNF) in two syngeneic immunocompetent mouse models of cancer. We observed complete tumor eradications when L19-IL2 was used in combination with CTLA-4 blockade. Interestingly, mice cured from F9 tumors developed new lesions when rechallenged with tumor cells after therapy, whereas mice cured from CT26 tumors were resistant to tumor rechallenge. Similarly, L19-IL2 induced complete remissions when administered in a single intratumoral injection in combination with L19-TNF, whereas the two components did not lead to cures when administered as single agents. These findings provide a rationale for combination trials in melanoma, as the individual therapeutic agents have been extensively studied in clinical trials, and the antigen recognized by the L19 antibody has an identical sequence in mouse and man.
authors.affiliation: Philochem AG, Libernstrasse 3, Otelfingen, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwager
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zürich, Zurich, Switzerland.
authors.forename: Teresa
authors.initials: T
authors.lastname: Hemmerle
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zürich, Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Aebischer
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zürich, Zurich, Switzerland. Electronic address: dario.neri@pharma.ethz.ch.
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy; D018243:Teratocarcinoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; C554817:L19-IL2 immunocytokine; C558733:L19mTNFalpha protein; D011993:Recombinant Fusion Proteins