title: Intratumoral hu14.18-IL-2 (IC) induces local and systemic antitumor effects that involve both activated T and NK cells as well as enhanced IC retention.
abstract: hu14.18-IL-2 (IC) is an immunocytokine consisting of human IL-2 linked to hu14.18 mAb, which recognizes the GD2 disialoganglioside. Phase 2 clinical trials of i.v. hu14.18-IL-2 (i.v.-IC) in neuroblastoma and melanoma are underway and have already demonstrated activity in neuroblastoma. We showed previously that intratumoral hu14.18-IL-2 (IT-IC) results in enhanced antitumor activity in mouse models compared with i.v.-IC. The studies presented in this article were designed to determine the mechanisms involved in this enhanced activity and to support the future clinical testing of intratumoral administration of immunocytokines. Improved survival and inhibition of growth of both local and distant tumors were observed in A/J mice bearing s.c. NXS2 neuroblastomas treated with IT-IC compared with those treated with i.v.-IC or control mice. The local and systemic antitumor effects of IT-IC were inhibited by depletion of NK cells or T cells. IT-IC resulted in increased NKG2D receptors on intratumoral NKG2A/C/E⁺ NKp46⁺ NK cells and NKG2A/C/E⁺ CD8⁺ T cells compared with control mice or mice treated with i.v.-IC. NKG2D levels were augmented more in tumor-infiltrating lymphocytes compared with splenocytes, supporting the localized nature of the intratumoral changes induced by IT-IC treatment. Prolonged retention of IC at the tumor site was seen with IT-IC compared with i.v.-IC. Overall, IT-IC resulted in increased numbers of activated T and NK cells within tumors, better IC retention in the tumor, enhanced inhibition of tumor growth, and improved survival compared with i.v.-IC.
authors: Department of Human Oncology, University of Wisconsin, Madison, WI 53705, USA.
authors: Richard K
authors: RK
authors: Yang
authors: Nicholas A
authors: NA
authors: Kalogriopoulos
authors: Alexander L
authors: AL
authors: Rakhmilevich
authors: Erik A
authors: EA
authors: Ranheim
authors: Songwon
authors: S
authors: Seo
authors: Kyungmann
authors: K
authors: Kim
authors: Kory L
authors: KL
authors: Alderson
authors: Jacek
authors: J
authors: Gan
authors: Ralph A
authors: RA
authors: Reisfeld
authors: Stephen D
authors: SD
authors: Gillies
authors: Jacquelyn A
authors: JA
authors: Hank
authors: Paul M
authors: PM
authors: Sondel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; C554817:L19-IL2 immunocytokine; D011993:Recombinant Fusion Proteins