INTERLEUKIN-2 AND INTERLEUKIN-7 AUGMENT THE CYTOLYTIC ACTIVITY AND EXPAND THE ANTITUMOR KILLING SPECTRUM OF ALPHA-CD3-INDUCED ACTIVATED KILLER-CELLS - POTENTIAL USE IN THE IMMUNOTHERAPY OF NONIMMUNOGENIC TUMORS

This study investigates the effect of different cytokines on the growt h and antitumor activity of the a CD3-induced killer cells CD3-AK, and the potential of the use of CD3-AK cells in cancer immunotherapy. Eig ht cytokines were tested. Only three (interleukin-2, -4 and 7) were ab le to support the growth of CD3-AK cells, which selectively killed dif ferent tumor targets of diversified origin. Culturing in interleukin-4 (IL-4) or IL-7 alone could maintain the growth of CD3-AK cells for 6- 8 days. Only IL-2 could maintain long-term growth, but further additio n of IL-4 exerted an inhibitory effect, which terminated the cell grow th in 2 weeks. In contrast, despite the fact that 11,-7 inhibited the proliferation of CD3-AK cells cultured in IL-2, as determined by [H-3] thymidine uptake, the recovery of viable cells was not reduced. In 10 days, CD3-AK cells cultured in IL-2 alone or IL-2 plus IL-7 increased 160- or 176-fold respectively. There is an inverse relationship betwee n the in vitro growth ability and Fas expression on the CD3-AK cells. Further, IL-7 increased the cytolytic activity of the CD3-AK cells two - to threefold. CD3-AK cells could be maintained in IL-2 or IL-2 plus IL-7 for 60-240 days or more. The long-term-cultured CD3-AK cells not only possessed a high level of cytolytic activity, but also showed a w ide spectrum of killing with different tumor targets; the normally ''r esistant'' targets, such as EL-4 lymphoma, fibrosarcoma, or melanoma, became susceptible. When the in vivo antitumor activity of the CD3-AK cells against a non-immunogenic tumor, EL-4, was tested by tumor-neutr alization experiments, we found that only the long-term-cultured cells gave significant protection, with those maintained in both IL-2 and I L-7 giving the highest degree of protection. Thus, these long-term-cul tured CD3-AK cells may have the potential to be used for immunotherapy of a variety of tumors whatever their immunogenicity.