Intracranial administrations of single or multiple source allogeneic cytotoxic T lymphocytes: chronic therapy for primary brain tumors

Abstract

Previous investigations by our group demonstrated the efficacy of single source allogeneic cytotoxic T lymphocytes (CTLs) given multiple times in reducing or curing tumor burden in the rat 9L gliosarcoma model. In this study, the lack of toxicity to normal brain when single source allogeneic CTLs were intracranially administered multiple times is documented. Additionally, the efficacy and lack of toxicity of allogeneic CTLs from multiple sources, each given once is documented. CTLs sensitized to Fischer antigen were prepared from major histocompatibility complex incompatible DA, PVG, Sprague-Dawley and Wistar-Furth rat lymphocytes. CTLs from multiple donors were administered one time each to Fischer rats bearing established 9L tumor at staggered intervals over a two week period and survival was monitored in relation to a sham treated group. Additional groups of nontumor-bearing rats received either multiple source allogeneic CTLs or single source DA anti Fischer CTLs in the same treatment regimen. Histological evaluation of the nontumor-bearing brains receiving either single or multiple source allogeneic CTL infusions showed minimal localized brain damage confined to the cannulation tract. No neuronal loss or inflammatory reaction was seen either adjacent to or remote from the administration site. Brains from the long-term survivors of the tumor-bearing animals showed no residual neoplasm; the instillation site had focal sterile abscesses; gliosis and neuronal loss did not extend into adjacent brain. The safety and potential of chronic, local allogeneic CTL administration, derived from multiple donors, as adjuvant local therapy for brain tumors was demonstrated.

Systemic T cell adoptive immunotherapy of malignant gliomas

“…3 To overcome the problem of migration to malignant brain tumors, intracavitary infusion of LAK cells or allogeneic CTL cytotoxic T lymphocytes and IL-2 has been used in a number of clinical trials. 3,4,18,23,25,27,32,40,50 However, the results of these studies have been uniformly disappointing. Apparently, the mere presence of activated T cells in the tumor cavity is not sufficient to mediate tumor regression.…”

Immunologic approaches to therapy for brain tumors

“…We reasoned that alloreactive CTL administered into the brain, an immunologically semiprivileged site, should be able to evade destruction by the host immune system long enough to give them time to actively destroy the tumor. Preclinical studies demonstrated the efficacy of this approach [42,43,45], and the development of human alloreactive CTL was refined in artificial capillary systems [51].…”

“…Our own laboratory has actively explored permutations of local adoptive immunotherapy for human malignant gliomas involving various effector cell types, including autologous lectin-stimulated and LAK cells [12,39], an allogeneic, irradiated cytotoxic T-cell line termed TALL-104 [40,41], and alloreactive CTL [42][43][44][45][46][47]. An allogeneic source for effectors holds the advantage of supply coming from an unrelated donor, rather than the immunosuppressed tumor-bearing individual, who may also be on immunosuppressive steroid treatment for control of brain edema.…”

Activated lymph node T cells for systemic adoptive immunotherapy of malignant glioma

“…[3] To overcome the problem of migration to malignant brain tumors, intracavitary infusion of LAK cells or allogeneic cytotoxic T lymphocytes and IL-2 has been used in a number of clinical trials. [3,4,18,23,25,27,32,40,50] However, the results of these studies have been uniformly disappointing. Apparently, the mere presence of activated T cells in the tumor cavity is not sufficient to mediate tumor regression.…”