Isolation and characterization of a metastatic Eb-like tumor variant highly responsive to interleukin (IL)-2 and to combination cytokine therapy with IL-2/IL-1 beta and IL-1 beta/interferon-alpha/beta.

In this study, we describe the origin and characterization of a new metastatic tumor cell line (p11-R-Eb) obtained after i.p. passages of the nonmetastatic Eb lymphoma cells into DBA/2 mice. The p11-R-Eb cells exhibited the same morphology and in vitro growth properties and chromosome markers as the original Eb cells. FACS analysis of the p11-R-Eb cells also revealed a close similarity to the Eb cells. Moreover, the p11-R-Eb cells were specifically killed by anti-Eb cytotoxic lymphocytes. In spite of all these characteristics of the Eb line, p11-R-Eb cells metastasized to the liver when injected i.v. or s.c. in DBA/2 mice. Peritumoral interleukin (IL)-2 treatment resulted in a potent antitumor response in DBA/2 mice transplanted s.c. with p11-R-Eb cells. In contrast, the same IL-2 regimen did not significantly increase the survival time of mice transplanted with the highly metastatic ESb cell line. Combined IL-1/IL-2 treatments of established p11-R-Eb tumors resulted in a synergistic antitumor effect and in tumor regression in 70% of the injected mice. Similarly, combined peritumoral treatment with IL-1 and interferon-alpha/beta, which were poorly effective or ineffective as single cytokine therapy, resulted in a marked antitumor effect, and 30% of the mice were cured. Spleen cells from IL-1/IL-2-treated p11-R-Eb-cell-injected mice showed a marked antitumor activity when assayed in a Winn assay with homologous tumor cells. This antitumor activity was eliminated by preincubation of spleen cells with antibodies to CD4 and complement and markedly inhibited by anti-asialo GM1 antibodies. P11-R-Eb cells represent, therefore, a new tumor model which may be useful for investigating the relevant mechanisms which need to be activated to achieve a potent antitumor response to cytokine therapy in the DBA/2 mouse host.