Unique Characteristics Associated with Systemic Adoptive Immunotherapy of Experimental Intracerebral Tumors

Abstract

Tumor-draining lymph node (LN) cells can be activated and expanded by stimulation with anti-CD3 followed by culture in interleukin-2 (IL-2) to acquire antitumor reactivity. Despite the lack of overt in vitro cytotoxicity, these effector cells mediate potent antitumor effects in the adoptive immunotherapy of established visceral tumors. Recently, we further demonstrated the therapeutic efficacy of anti-CD3/IL-2-activated tumor-draining LN cells for the treatment of intracerebral tumors in a neutralization assay as well as by local and systemic adoptive transfer. In this study, we analyzed the immunologic specificity, cellular requirements, and conditions that could promote the therapeutic effectiveness of the systemically transferred tumor-reactive cells. Using two antigenically distinct murine fibrosarcomas, MCA 205 and MCA 207, the adoptive immunotherapy of intracerebral tumors was immunologically specific, which was apparently determined by the tumor that stimulated the draining LN. Analysis of effector cells revealed the involvement of both CD4 + and CD8 + T cells for successful therapy. Therapeutic efficacy of the transferred cells was greatly enhanced if the tumor-bearing host was also treated with sublethal whole-body irradiation (500 cGy). However, unlike the treatment of tumors located in visceral organs, the administration of exogenous IL-2 consistently inhibited the antitumor reactivity of the transferred cells against intracerebral tumors. These results demonstrate the feasibility of treating brain tumors by systemic adoptive T-cell therapy, although the conditions for efficient treatment appear to be different from those required for visceral tumors.