Immunological responsiveness to interleukin-2-producing brain tumors can be restored by concurrent subcutaneous transplantation of the same tumors

Abstract

The central nervous system shows tolerance for activated host immune reactions, and this relative unresponsiveness may lessen the efficacy of an immunotherapy for brain tumors. Using interleukin-2 (IL-2)-producing 9L rat gliosarcoma cells (9L/IL-2), we examined whether secretion of IL-2 from subcutaneous (s.c.) and/or intracerebral (i.c.) tumors can elicit augmented immunological responses to brain tumors. Syngeneic rats could reject 9L/IL-2 cells inoculated s.c., but developed 9L/IL-2 brain tumors by i.c. inoculation. The growth of i.c. 9L/IL-2 tumors was, however, significantly retarded compared with that of i.c. wild-type tumors. The growth of i.c. wild-type tumors was significantly suppressed when the rats concurrently received 9L/IL-2 cells s.c. Moreover, most of the rats that were inoculated i.c. with 9L/IL-2 cells did not develop brain tumors when concurrently injected s.c. with 9L/IL-2 cells. Immunohistochemical analysis on i.c. 9L/IL-2 tumors, when the rats were concurrently inoculated s.c. with 9L/IL-2 cells, revealed that migration of CD4 ϩ or CD8 ϩ T cells, monocytes/microglias, and macrophages was markedly augmented to a similar level as found in the s.c. 9L/IL-2 tumors. These results showed that systemic immune responses to brain tumor were induced in an immunologically privileged site by concurrent s.c. inoculation of the same tumors that produce IL-2. The present study may also raise the possibility of a therapeutic strategy for brain tumors by the combinatory expression of IL-2 gene using s.c. immunization followed by direct gene transfer into brain tumors.

Local tumor irradiation augments the antitumor effect of cytokine-producing autologous cancer cell vaccines in a murine glioma model

“…We have found that from the wide panel of cytokines, only IL -2 -, 8 IL -4 -, IL -12 -, 8 and GM -CSF -secreting vaccines prolonged lifetime and cured substantial proportion of glioma -bearing mice. This is in good agreement with previous findings that GM -CSF, 15 -17,28,30 IL-4, 15,18,19,22,25 IL -12, 21,24 or IL -2 21,23,3133 production by cancer cells is in association with prolonged antitumor effect.…”

Recombinant Sendai Virus Vector Induces Complete Remission of Established Brain Tumors through Efficient Interleukin-2 Gene Transfer in Vaccinated Rats

“…This experimental brain tumor model using 9L cells has a quite stable property; the animals are 100% fatal between 18 and 25 days after inoculation and all the untreated tumors are visible by MRI on day 7 with a mean size of 8.0 F 6.0 mm 3 (16,17). When treated with hIL2-SeV/DMDF and the vaccination, the observed tumor volumes on day 21 were not different between the eliminated tumors and the other progressing tumors.…”

“…transplantation of interleukin 2 (IL-2) -producing cells in the rat brain tumor model (16,17). For clinical application of the cytokine gene therapy strategy, however, the cell-mediated therapy needs a large amount of cytokine-producing cells to cover the whole tumor areas in the human brain.…”

Combining Cytotoxic and Immune-Mediated Gene Therapy to Treat Brain Tumors

“…When syngeneic 9L tumor cells engineered to express IL-2 were introduced into the CNS of rats, it was found that tumors developed in the CNS. These grew more slowly than wild-type tumors, but all of the animals eventually succumbed to the disease irrespective of IL-2 expression [130]. It was later found by the same group that IL-2 producing cells transplanted into the CNS could effectively eliminate established tumors by inducing immunity in peripheral tissues.…”