Successful Treatment of a Malignant Rat Glioma with Cytotoxic T Lymphocytes

Abstract

Brain tumors are highly resistant to therapy. Their diffuse infiltrative nature and the relative inaccessibility of brain tissue to blood and lymph are barriers to surgical and cytotoxic treatments alike. The purpose of this study was to produce immune cells specifically reactive with an anaplastic rat glioma (RT2) and determine whether those cells could affect tumor progression in the brain. RT2-specific cytotoxic cells were prepared by priming rats in vivo with RT2 tumor cells and Corynebacterium parvum and stimulating the primed lymphocytes in vitro with irradiated RT2 tumor cells and interleukin-2 (IL-2). Cultured cells exhibited a high level of cytotoxicity against RT2, but not C6 (an allogeneic glioma), 3M2N (a syngeneic mammary tumor), or CSE (a syngeneic fibrosarcoma) tumor cells. To generate a model for therapy, rats were injected intracerebrally with RT2, generating progressing brain tumors, which killed untreated rats in approximately 2 weeks. To test the therapeutic potential of the effector cells, tumor-bearing rats were treated by intravenous injection of lymphocytes on Day 5 of tumor growth. Treated rats also received a 5-day course of systemic IL-2 beginning on Day 5. Treatment with IL-2 alone, RT2-primed spleen cells, or RT2-primed spleen cells stimulated in vitro with C6 did not affect rat survival. However, tumor-bearing rats treated with RT2-stimulated lymphocytes exhibited increased survival or were cured. Systemic IL-2 was an essential adjunct, because survival was not affected by treatment with effector cells alone. Therapy initiated on Day 8 of tumor progression lacked effect on survival.(ABSTRACT TRUNCATED AT 250 WORDS)

In Vivo Intracellular Oxygen Dynamics in Murine Brain Glioma and Immunotherapeutic Response of Cytotoxic T Cells Observed by Fluorine-19 Magnetic Resonance Imaging

“…Taking advantage of the body's own defense system, immunotherapeutic strategies specifically target tumor cells without damaging the surrounding healthy tissue [7], [28]. Existing immune therapy regimes can be categorized into three major types, i.e., general immunomodulation [29], [30], cancer vaccines [5], [31], [32], and adoptive cell transfer (ACT) [3], [33]. In ACT therapies, the TILs are harvested from the body, expanded and stimulated ex vivo , then transferred back to the host to elicit an immune response against malignancies.…”

“…Immunotherapy using live cells has opened up new avenues for targeting brain tumors with minimal damage to healthy tissues [3], [4], [5], [6], [7]. We recently demonstrated that following intravenous transfer of ex vivo activated tumor-specific Tc1, but not Tc2, cytotoxic CD8+ T cells traffic to CNS tumor sites and mediate a potent CNS anti-tumor response [8].…”

Glioblastoma multiforme: The terminator

“…Until recently, animal models for gliomas have consisted of clonal glioma cell lines, maintained in culture, that are injected in the flanks or brains of rodents. These cells grow into mass lesions that eventually kill the animals (9,10). To what extent either the genetic alterations selected for during passage of the cells in culture or the interactions between tumor cells and the host tissues in these experimental gliomas represents the biology of human gliomas is questionable, especially in the area of immune rejection.…”

Biomarkers for glioma immunotherapy: the next generation

“…Following preclinical studies confirming the survival, localization, and persistent anti-tumor specificity of autologous stimulated glioma-infiltrating lymphocytes [23], Holladay et al tested the ability of autologous monocytes pre-loaded with irradiated autologous tumor cells and stimulated with IL-2 to selectively expand CD4 + and CD8 + T cells, compared to simple vaccination with such autologous irradiated tumor cells and adjuvant, first in a rodent model, then human patients. Although treatment was well tolerated in both arms of the clinical trial, and tumor regression and improved survival were observed among a subset of patients, there was no retrospective analysis of potential immune biomarkers associated with treatment responses [24, 25]. …”