Interleukin 1 as an Adjuvant for Active Specific Immunotherapy in a Murine Tumor Model1

Many vaccines are dependent on adjuvants to augment the immunizing process. The vaccines being developed for active specific immunotherapy of cancer have also usually included an adjuvant in the clinical studies. Several cytokines have been identified which are participants in the immune response to new antigenic stimulation. We investigated the potential of intcrleukin 1 (IL-1 ) to serve as an adjuvant when administered either locally with the vaccine or given systemically. Using a weakly immunogenic syngeneic murine lung cancer tumor system (Line 1, BALB/cByJ mice), we have administered recombinant human II -1«. recombinant human IL-1/3, and the peptide fragment 163171 of 11-l,i in combination with a vaccine of radiated tumor cells. We demonstrated an improved vaccine effectiveness with all three types of IL-1 molecules. The effect was both dose dependent and duration de pendent (the number of daily doses given). When IL-1 was administered at a site remote from the vaccine, it functioned as well as when adminis tered at the vaccine site indicating that IL-1 functions as a systemic adjuvant. A requirement for administering the IL-1 during the 10-day period following the vaccine, rather than later, was observed. A detri mental effect on weight gain was seen with high doses of IL-la, 11-1,1 and the peptide but some lower doses were effective in the adjuvant function without impairing weight gain. When eight daily doses of IL-1 were given following the vaccine, 7011)0'i of the mice became tumor free, while mice receiving vaccine alone were only 0-20% tumor free. We conclude that IL-1 appears promising as an adjuvant to vaccines and is highly effective in this model of active specific immunotherapy for cancer. i.d.-' or s.c. B. Calmette-Guérinand C. parvum have been used as local adjuvants in animal and clinical studies of tumor vaccines. IL-2 has been studied as a systemically administered adjuvant. It has been given as daily or twice daily injections or as continuous infusions over ten days, in close approximation to the day on which the vaccine is given. Interleukin 2 has been effective with a pleuropneumonia vaccine for pigs (9), in a rabies virus vaccine assay in mice (9), with a Herpesvirus vaccine in guinea pigs (10), and with a cancer vaccine in mice (11). We selected IL-1 for investigation as a candidate adjuvant for tumor vaccines. Both natural and recombinant molecules of IL-1 are potent activators of Tand B-lymphocytes. IL-1 ap pears to be critical in amplifying the response to specific anti gens and mitogens (12). Several agents used as local adjuvants have been found to increase IL-1 production or are suspected to function via IL-1. These include lentinan (13), muramyl dipeptide (14), lipopolysaccharide (15), RU 41.740 (an extract of Klebsiella pneumoniae) (16), aluminum hydroxide (17), bacterial peptidoglycans (18), and tuftsin (19). In previous studies we demonstrated that a multilymphokine supernatant could serve an adjuvant function when adminis tered with a tumor vaccine (20). We are reporting now on our experiments which indicate that IL-1, when used alone, is a strong adjuvant in a model of active specific immunotherapy for cancer.