During the past several years data from two different lines of investigation have converged to suggest a new and potentially useful approach to immunotherapy of cancer. One line of investigation deals with the finding on human and animal tumor cells of alien histocompatibility antigens; antigens which either crossreact with or are identical to histocompatibility antigens found on normal cells of allogeneic individuals. The second line of investigation has demonstrated that cell mediated reactivity against tumors can be induced by immunization of syngeneic hosts in vivo or activation of their cells in vitro with normal allogeneic cells. We seek to demonstrate whether alloimmunization will be a worthwhile approach for the immunotherapy of cancer. In the proposed research we will address several unanswered critical questions by testing three hypotheses experimentally in mice: First, whether alloimmunization induces antitumor immunity by an antigen-specific mechanism with alien histocompatibility antigens on cancer cells serving as targets for immunological killing; second, whether cytotoxic T lymphocytes, helper T lymphocytes, NK or NK-like cells or other cellular effector mechanisms are responsible for alloimmunization-induced antitumor reactivity; and third, whether tumors expressing genetically inappropriate H-2 K/D alloantigens escape rejection by their syngeneic hosts because the tumors lack an H-2 I-region alloantigenic stimulus for induction of the cellular effector mechanism. In vivo tests of allograft and antitumor immunity as well as in vitro assays of cell-mediated cytotoxicity will be used to test these hypotheses. We are hopeful that insights gained in these studies will help establish biological principles which can be used to develop strategies for successful immunotherapy of human malignancies.