We have extended our investigation of tumor abrogation in vivo by human lymphocytes retargeted by heterocrosslinked antibodies to react with a human ovarian carcinoma cell line. Using an athymic mouse model in which intraperitoneal growth of established tumor is treated with retargeted human lymphocytes, cumulative results of a dozen experiments have confirmed that crosslinking the T-cell receptor complex, expressed by T lymphocytes, to tumor cells markedly enhances tumor abrogation relative to lymphocytes alone or to crosslinked antibodies alone. Moreover, results of a variety of additional controls carried out in vivo have confirmed that the heterocrosslinked antibodies indeed facilitate tumor abrogation (collaborative effort with Dr. D. Segal, see project no. ZOl CB 09254-14 E). Two aspects of our understanding of mouse activated killer (AK) lymphocytes, activated in vitro to react against a wide variety of tumors in a fashion not restricted by MHC, have been advanced this year. First, the mechanism(s) for generating AK cells against tumor cells has been clarified by finding that LPS-related molecules serve as potent cofactors for induction of AK cells by selected macromolecular polyanions, such as dextran sulfate, fucoiden, and polyinosinic acid. The cofactors are not independently active, insofar as they induce little or no AK cell activity alone and enzymatic digestion of the polyanions abrogates generation of AK cells. Second, we have markedly enhanced the veto activity that accompanies thymocytes with IL-2 induced AK cell activity, by optimizing both the activation conditions and their use with in vitro allogeneic responses subject to veto activity. Veto activity establishes tolerance to foreign tissues. We anticipate that these findings will facilitate activation of lymphocyte antitumor activity in vivo and establishment of tolerance to foreign cells in vivo.
