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The Effect of Interleukin 12 Desensitization on the Antitumor Efficacy of Recombinant Interleukin 12¹

Biomedical Graduate Program [C. M. C.], The Wistar Institute [M. W., G. T., W. M. F. L.], Department of Medicine, Cancer Center [W. M. F. L.], and Institute for Human Gene Therapy [W. M. F. L.], University of Pennsylvania, Philadelphia, Pennsylvania 19104

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 (rIL-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- 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.

¹ W. M. F. L. is supported by grants from NIH and is a recipient of an American Cancer Society Faculty Research Award. G. T. and M. W. are supported by awards from NIH. C. M. C. is supported by the NIH Medical Scientist Training Program Grant.

² To whom requests for reprints should be addressed, at CRB 663, 415 Curie Boulevard, Philadelphia, PA 19104. Tel: (215) 898-0258; Fax: (215) 573-7912.

Received 12/ 9/96. Accepted 4/15/97.

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