title: Intratumoral immunocytokine treatment results in enhanced antitumor effects.
abstract: Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled (111)In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI, 53792, USA.
authors.forename: Erik E
authors.initials: EE
authors.lastname: Johnson
authors.forename: Hillary D
authors.initials: HD
authors.lastname: Lum
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
authors.forename: Brian E
authors.initials: BE
authors.lastname: Schmidt
authors.forename: Meghan
authors.initials: M
authors.lastname: Furlong
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Buhtoiarov
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Hank
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: David
authors.initials: D
authors.lastname: Colcher
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins