Prolongation of survival of mice with glioma treated with semiallogeneic fibroblasts secreting interleukin-2

OBJECT: The current prognosis for patients with malignant brain tumors rema ins poor, and new therapeutic options are urgently needed. We previously ha ve shown that prolongation of survival can be achieved in C57BL/6 mice (H-2 (b)) with a syngeneic intracerebral or subcutaneous glioma when treated wit h allogeneic mouse fibroblasts (H-2(k)) genetically engineered to secrete i nterleukin-2 (IL-2). Like other antigens, tumor-associated antigens are rec ognized by cytotoxic T lymphocytes in the context of determinants specified by the major histocompatibility complex class I locus. Because the rejecti on of allogeneic major histocompatibility complex determinants has the prop erty of an immune adjuvant, immunotherapy of glioma with a cellular immunog en that combines the expression of both syngeneic class I determinants and allogeneic antigens could have advantages over an immunogen that expresses syngeneic or allogeneic determinants alone. METHODS: To investigate this question in a mouse glioma model, we further m odified allogeneic mouse fibroblasts (H-2(k)), not only for IL-2 secretion, but also for the expression of H-2K(b) class determinants. We tested the i mmunotherapeutic properties of these semiallogeneic cells (LM-IL-2/H-2K(b)) in C57BL/6 mice with Gl261 glioma in both subcutaneous and intracerebral g lioma models. RESULTS: C57BL/6 mice with either a subcutaneous or intracerebral glioma tr eated solely by injection of these IL-2-secreting semiallogeneic cells had significantly prolonged survival rates compared with untreated mice or mice treated with cells secreting only IL-2 or cells lacking the H-2K(b) determ inants. In some instances, the mice treated with the semiallogeneic cells s urvived indefinitely, suggesting total eradication of the glioma. When a Cr -51 release assay was used, the specific immunocytotoxicity measured by rel ease of isotopes from labeled Gl261 glioma cells coincubated with spleen ce lls from mice immunized with the semiallogeneic IL-2-secreting cells was si gnificantly higher than that of spleen cells from nonimmunized mice or mice immunized with allogeneic cells lacking syngeneic major histocompatibility complex determinants. In addition, antibody depletion studies using monocl onal antibodies against CD8(+) and natural killer/lymphokine-activated kill er cells demonstrated a specific CD8(+) immunocytotoxic response in animals immunized with the semiallogeneic IL-2-secreting cells compared with only a natural killer/lymphokine-activated killer response in mice immunized wit h the allogeneic IL-2-secreting cells. CONCLUSION: The augmented immune response against glioma in mice treated wi th the semiallogeneic IL-2-secreting cells points toward a new form of immu notherapy, "immuno-gene therapy," for patients with malignant intracerebral glioma.