Adoptive Immunotherapy for Malignant Brain Tumors Using Killer T Lymphocytes Enhanced by Interferon Gamma Gene Transfer

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A mouse ihterfebon (IFN) gamma CDNA was transferred to mouse neuroblastoma cell line, C1300 of A/Jax origin, with a chimeric retrovirus containing the IFN gamma gene. Two infected subclones C-gamma-3 and C-gamma-22 were obtained as a low and a high producers, respectively. These subclones were similar to the original clone in respects of in vitro growth pattern, morphology, and antigen expression of neurofilaments, except the expression of major hisiocompatibility complex (MHC) class I antigens, which were extremely augmented at the surface expression level as well as at the transcription level, regardless the difference in amount of their IFN-gamma production. The in vivo tumorigenicity was reduced in the high producer, C-gamma-22, but not in the low producer, C-gamma-3. The in vivo tumor growth rate was suppressed in both subclones, as compared to the parental line. It was therefore suggested that the suppression of tumor formation is more closely associated with constitutive IFN-gam … More ma production rather than the MHC antigen expression, and that the tumor growth rate is affected by the high expression of the surface antigens.As a next step, the cDNA encoding mouse IFN-gamma was transferred into a specific cytotoxic T lymphocyte (CTL) clone, designated E-4, against 203-glioma (a 20- methylcholanthrene-induced glioma line of C57/BL mouse origin). The efficacy of IFN-gamma production from the exogenous gene on augumeniation of tumor targeting was confirmed. Out of five, two gene-transferred subclones constitutively produced 8 to 10 times higher amount of IFN-gamma as compared with the parental E-4. Correspondingly, these two subclones exhibited 2 to 3 times higher killing activity against 203-glioma as compared with the parental line. It was thought that tumor cells, in the vicinity of the constitutively IFN-gamma-producing CTLs, may be stimulated to induce or enhance the expression of surface antigens, including the MHC antigens as well as the tumor associated antigens relevant to immune recognition.In summary, it was hopefully suggested that retrovirus-mediated transfer of cytokine genes would be useful for a modified immunotherapy of cancer. Less