Gamma-irradiation suppresses T-cell mediated protective immunity against a metastatic tumor in the afferent phase of the immune-response but enhances it in the efferent phase when given before immune cell transfer.

Using a metastasizing animal tumor as a model we describe experimental conditions for obtaining either synergistic or antagonistic effects between host irradiation and T cell mediated antitumor immunity. The results were obtained in the well defined murine lymphoma ESb which is a spontaneous highly metastatic tumor variant expressing a tumor associated antigen that can induce protective immunity and tumor specific cytotoxic T lymphocyte (CTL) activity. Sublethal irradiation of mice during the afferent (induction) phase but not during the efferent (effector) phase of the antitumor immune response had a strong suppressive effect on protective immunity. The radiation mediated defect could be reconstituted by transfer of immune spleen cells. The immune system of syngeneic (DBA/2) and allogeneic (B10.D2) mice changed within 24 h after first contact with the ESb tumor cells from radio-sensitivity to radio-resistance possibly reflecting an active cellular response associated with the change from virgin to an antigen sensitized (primed) state of T lymphocyte differentiation. T cell depletion experiments revealed that the afferent phase was dependent on both CD4 and CD8 host T lymphocytes while the efferent phase was mainly CD8 T cell dependent. A synergistic effect between gamma-irradiation and antitumor immunity was observed in adoptive immunotherapy experiments. When tumor-bearing hosts were irradiated before intravenous transfer of either syngeneic or allogeneic antitumor immune T cells the expression of anti-metastatic protective immunity was greatly enhanced in comparison to identically treated non-irradiated hosts.

Effective immune rejection of advanced metastasized cancer.

A cellular cancer therapy is described with unique efficiency even in late-stage disease. in situ activated tumor-immune T cells, induced in allogeneic, tumor-resistant, MHC identical but superantigen different donor mice (B10.D2) could transfer strong graft-versus-leukemia (GvL) effects accompanied by only mild graft-versus-host (GvH) reactivity. Systemic immune cell transfer into 5 Gy irradiated DBA/2 mice bearing up to 4 week established syngeneic tumors and macrometastases led to massive infiltration of tumor tissues by CD4 and CD8 donor T lymphocytes. Upon interaction of immune CD4 donor T cells with host antigen presenting cells in synergy with immune CD8 donor T cells attacking the tumor cells directly, primary tumors (1.5 cm diameter) were encapsulated and rejected from the skin and liver metastases eradicated. For the first time, such adoptive cellular immunotherapy (ADI) was followed in individual live animals by P-31-NMR spectroscopy of primary tumors. An approximately 25,000 fold excess of metastatic tumor cells could be rejected as revealed quantitatively by FACScan analysis of lacZ gene transfected tumor cells.