Drug-mediated Increase of Tumor Immunogenicity in Vivo for a New Approach to Experimental Cancer Immunotherapy¹

In vivo treatment of leukemic mice with the antitumor agent 5-(3,3′-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) results in early increase of tumor-associated immunogenicity which is expected to evoke host-versus-graft responses. However, transplantation immunity is severely impaired in DTIC-treated mice due to the immunodepressant activity of the drug. It follows that the DTIC-mediated increase of tumor immunogenicity effect cannot be of therapeutic value in ordinary conditions. In the present report, we describe the results of studies aimed at restoring immunocompetence of DTIC-treated mice by means of adoptive transfer of syngeneic lymphoid cells. Infusion of spleen cells into DTIC-treated mice failed to restore graft responsiveness even in allogeneic tumor-host combinations. However, when DTIC treatment was followed by administration of cytotoxic alkylating agents such as cyclophosphamide (CY) or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), graft responsiveness was partially restored upon adoptive transfer of syngeneic splenocytes. (BALB/c × DBA/2) F₁ (hereafter called CD2F₁) mice bearing leukemia L1210 Ha were treated as follows: (a) DTIC for increasing the immunogenicity of the leukemic cells; (b) CY or BCNU; and (c) adoptive transfer of CD2F₁ lymphocytes. The results showed that: (a) DTIC alone or DTIC plus spleen cells produced little or no increase in survival times with respect to untreated controls; (b) DTIC plus CY or BCNU increased survival times to a larger extent; and (c) the adoptive transfer of lymphocytes produced marked protection of leukemic mice when the hosts had been pretreated with DTIC plus CY or BCNU but not with CY or BCNU without DTIC. These data may provide a model for exploiting DTIC-induced increase of tumor immunogenicity for immunochemotherapeutic regimens.