Synergistic interleukin-18 and low-dose interleukin-2 promote regression of established murine neuroblastoma in vivo.
OBJECTIVE
Severe systemic toxicities have limited the clinical applications of the potent cytokine, interleukin-2 (IL-2). Recent studies have shown that IL-18 synergizes with IL-2 to enhance cytolytic activity in vitro. Combination therapy allows for IL-2 dose reduction, thus, limiting its toxicity while augmenting natural killer cell activity. The authors hypothesize that IL-18 plus low-dose IL-2 may induce a potent and sustained antitumor response in vivo providing effective immunotherapy for neuroblastoma.


METHODS
Four groups of A/J mice (n = 28) were inoculated subcutaneously in the right flank with 1 x 10(6) murine neuroblastoma cells (TBJ). On day 7, 5 consecutive daily peritumoral injections were performed with saline (control), human rIL-2 (30,000 IU), murine IL-18 (1 microg), or IL-2 plus IL-18. Tumor growth was monitored, and animals with tumor progression were killed on day 21. Seven weeks after the initial treatment, animals with rejected tumors were rechallenged with 5 x 10(6) cells in the opposite flank. Quantitative data were analyzed by Student's t test.


RESULTS
Rapid tumor growth and death was noted in all control animals by 21 days. Complete tumor eradication was seen in 28% of mice treated with IL-2 (P =.03), 42% of mice treated with IL-18 (P <.05), and 57% of mice treated with of IL-2 plus IL-18 (P <.05). Despite the initial response, all animals failed rechallenge and developed new or recurrent tumors within 7 to 10 days.


CONCLUSIONS
Coadministration of low-dose IL-2 plus IL-18 induced a potent primary response to murine neuroblastoma likely caused by activation of natural killer cells in the tumor microenvironment. This combined cytokine therapy strategy was unable to induce sustained immunity to rechallenge. However, dendritic cell vaccination combined with IL-2 plus IL-18 cytokine treatment did allow for the establishment of a complete and durable antitumor response.
Redlinger
Richard E
RE
Department of Surgery, University of Pittsburgh School of Medicine, Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213-2583, USA.
Mailliard
Robbie B
RB
Lotze
Michael T
MT
Barksdale
Edward M
EM
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology; D004354:Drug Screening Assays, Antitumor; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D020382:Interleukin-18; D007376:Interleukin-2; D011994:Recombinant Proteins; D007371:Interferon-gamma