The effect of interleukin 12 desensitization on the antitumor efficacy of recombinant interleukin 12.
Use of the cytokine interleukin 12 (IL-12) has been shown to enhance the rejection of a variety of murine tumors, but preclinical and clinical studies have revealed that recombinant IL-12 (rlL-12) can produce severe toxicity. In an effort to improve the tolerance and therapeutic effectiveness of this cytokine, we investigated the influence of giving a single dose of recombinant murine IL-12 (rmIL-12) a week prior to daily cytokine administration (predosing) on its toxic and antitumor effects. These studies were performed in C3H/HeN mice, in which a course of rmIL-12 at standard doses without predosing induced rejection of syngeneic K1735 melanomas in 33%, and in A/J mice, in which treatment induced rejection of syngeneic B7-1+ SCK (SCK.B7-1) mammary carcinomas in 63%. Administration of a predose of rmIL-12 markedly reduced cytokine toxicity in a dose-dependent manner and allowed safe administration of up to 8-fold higher doses of daily rmIL-12 in C3H/HeN mice and 4-fold higher doses of rmIL-12 in A/J mice. Predosing followed by either standard or high daily doses of rmIL-12 did not significantly alter most end points of rmIL-12 treatment of K1735 or SCK.B7-1 tumors (survival, death from tumor, development of protective immunity, and so on), but they appeared to attenuate early control of tumorigenesis by rmIL-12. Evidence for the latter comes from a shortening of the characteristic rmIL-12-induced delay in tumor appearance and in the frequent appearance of tumors that subsequently regress. However, higher doses appear to produce better therapeutic results than standard doses of rmIL-12 after predosing. Predosing severely blunted induction of serum IFN-gamma levels by rmIL-12, which probably accounts for many of the effects of predosing on rmIL-12 toxicity and efficacy. Thus, predosing desensitizes mice to the toxic effects of rIL-12 and allows much higher doses to be given but, despite this, it does not improve and, by some criteria, it attenuates rIL-12 therapeutic outcome. Our results do not support the use of predosing as a way to enhance the effectiveness of rIL-12 in cancer clinical trials.
Coughlin
C M
CM
Biomedical Graduate Program, University of Pennsylvania, Philadelphia 19104, USA.
Wysocka
M
M
Trinchieri
G
G
Lee
W M
WM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma