Evaluation of cytokine toxicity induced by vaccinia virus-mediated IL-2 and IL-12 antitumour immunotherapy.
Single intratumoural treatment of nude mice with a vaccinia virus (VV)-expressing interleukin-1 (IL-2) or IL-12 induced significant tumour growth inhibition associated with clear signs of toxicity. At a low virus dose, only some treated animals showed signs of toxicity. We characterized and compared the activity of NK and B cells and major pro-inflammatory factors (IFN-gamma, TNF-alpha) in treated animals with and without toxicity. One week after treatment animals exhibiting signs of cytokine-related toxicity showed dramatic increases in several measured parameters. High leukocyte and lymphocyte counts in blood and marked increases in NK and CD25(+)cells in both blood and spleen were associated with IL-2-induced toxicity, while IL-12-induced toxicity was related to a great elevation of CD25(+)cells in blood and CD71(+)cells in the spleen. In contrast, immune activation in animals free of toxicity was observed on day 2 after the treatment, which drastically declined by day 7. Thus, immune responses induced by IL-2 and IL-12 therapy appear to play important roles in both tumour inhibition and the accompanying toxicity. Short-term effects induced by IL-2 and IL-12 could be critical for antitumour therapy that prolongs survival and protects from adverse side effects.
Chen
B
B
Center for Molecular Biology and Gene Therapy, Department of Microbiology and Molecular Genetics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Timiryasova
T M
TM
Gridley
D S
DS
Andres
M L
ML
Dutta-Roy
R
R
Fodor
I
I
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000633:toxicity*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D009929:Organ Size; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011990:Receptors, Transferrin; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C068126:CD71 antigen; D016207:Cytokines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma