EFFECT OF INTERLEUKIN-1-ALPHA ON THE IN-VITRO ACTIVATION OF TUMOR-DRAINING LYMPH-NODE CELLS FOR ADOPTIVE IMMUNOTHERAPY

Adoptive immunotherapy using in vitro activated T-cells can mediate th e destruction of metastatic tumor deposits in animal models. These ant itumor effector cells can be generated from mice with subcutaneous tum or by the sequential in vitro activation of tumor-draining lymph node (TDLN) cells with monoclonal antibody to the T-cell receptor complex ( anti-CD3) and expansion in low concentrations of interleukin-2 (IL-2). In this animal model, the concomitant presence of visceral tumor can suppress the sensitization of tumor-reactive TDLN cells. We investigat ed whether IL-1 alpha added during in vitro activation and/or expansio n of TDLNs could augment their antitumor activity in adoptive therapy. Mice were inoculated subcutaneously with MCA 205 tumor. TDLN cells we re harvested and activated in vitro with 1 mu g/ml anti-CD3 for 2 days (anti-CD3 phase), followed by expansion in 10 U/ml IL-2 for 3 days (I L-2 phase). Experimental cultures had IL-1 (10-10,000 U/ml) added in e ither or both phases. After the 5-day culture period, cells were count ed to determine in vitro cellular proliferation and then adoptively tr ansferred to mice bearing 3-day established lung metastases to assess in vivo antitumor efficacy. IL-1 added during the anti-CD3 or IL-2 pha se did not alter in vitro cellular proliferation. The presence of IL-1 during the anti-CD3 phase led to the generation of cells that were si gnificantly more therapeutically efficacious than cells generated in t he absence of IL-1. The effect of IL-1 during anti-CD3 activation appe ared to be dose dependent in the concentration range 10-1,000 U/ml. Th e addition of IL-1 during the IL-2 phase only did not enhance the anti tumor reactivity of the activated cells. The beneficial effect of IL-1 during the anti-CD3 activation phase was specific for the tumor again st which the TDLN had been initially sensitized; also, there was no ev idence that nontumor bearer lymphocytes developed significant antitumo r reactivity when ''activated'' with IL-1 and anti-CD3. Furthermore, a ddition of IL-1 during the anti-CD3 activation phase abrogated suppres sion induced by the concomitant presence of lung metastases during sub cutaneous tumor growth. IL-1 appears to up-regulate the in vitro activ ation of tumor-reactive lymphocytes derived from TDLN, in both the pre sence and the absence of visceral metastases.