Analysis of interleukin 2 and various effector cell populations in adoptive immunotherapy of 9L rat gliosarcoma: allogeneic cytotoxic T lymphocytes prevent tumor take.

Abstract

Recombinant interleukin 2 (rIL-2) and various effector cell populations were used for adoptive immunotherapy in the Fischer strain 9L rat gliosarcoma model. The in vivo cytotoxicities of nonspecifically activated lymphocytes and specifically activated cytotoxic T lymphocytes (CTLs) were assessed in a modified in vivo neutralization (Winn) assay.Effector cells (106) those who received syngeneic unstimulated T lymphocytes and rIL-2. For a set of animals given the same inoculum of 9L tumor, significantly improved survival was shown for groups treated with nonadherent or adherent LAK cells (P < 0.0003), syngeneic CTLs (P = 0.0327), or allogeneic CTLs (P = 0.0025) over untreated control animals by using Mantel-Haenzel nonparametric logrank equations. Only treatment with allogeneic CTLs prevented tumor take.The rat 9L gliosarcoma model provides an efficient and rapid means to explore the efficacy of lymphokine and cellular therapy for brain tumors. It is derived from an inbred strain of Fischer rats, with a major histocompatibility complex haplotype of RTII'i (1, 2). Intracranially implanted 9L glioma cells grow in a predictable fashion in the syngeneic Fischer 344 rat (3). Rats bearing 9L tumor and given systemic recombinant interleukin 2 (rIL-2) therapy show a small increase in survival time compared to untreated control animals (4).Adoptive immunotherapy has been investigated in other brain tumor models. Lymphokine-activated killer (LAK) cells and rIL-2 were combined with the F98 rat glioma tumor 18 hr before implantation into the rat cerebrum and the rats exhibited an increased survival (5). Similarly, a clone of syngeneic tumor-sensitized cytotoxic T lymphocytes (CTLs) was partially effective in the immunotherapy of 203 glioma in an animal model (6). The in vivo antitumor activity of the clone has been demonstrated both in a Winn neutralization assay against 203 glioma cells inoculated intracranially and when administered intravenously 7 days after intracranial inoculation of 203 glioma. In rats bearing T9 gliosarcoma, LAK cells administered intravenously and intratumorally increased survival, but immune spleen cells did not (7). Likewise, LAK cells administered to Wistar rats bearing C6 glioma showed antitumor activity in vitro and in vivo (8).The implication that the brain is immunologically privileged was based on demonstrations that allogeneic and xenogeneic glioma cells were maintained intracranially (9). More recent studies have revealed some immunological response to these tumors (10, 11); thus, the brain is now considered to be a semiprivileged immune site. On that premise and because it has been shown that CTLs from an allogeneic source are more effective against tumor than those from a syngeneic source (12), we have investigated whether brain tumors in rats could be cured by local adoptive transfer. The advantage of using allogeneic CTLs for therapy ofglioma patients is that the cells are from a healthy donor. This circumvents collecting the patients' own cells for therapy, which would ex...

Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy.

“…Glioma cells express major histocompatibility complex class I and class II molecules (3), as well as tumor-associated antigens that have been demonstrated to stimulate anti-tumor immune responses and thus are good tumor vaccine candidates (4,5). However, several studies have demonstrated the secretion of an immunosuppressive factor by glioma cells that was subsequently identified as transforming growth factor P (TGF-/3) (6-9).…”

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

“…We have reported on the in vivo response of Interleukin-2 with various effector cell preparations activated to kill 9L gliosarcoma when locally adoptively transferred in the rat model system [3]. Nonspecifically-activated syngeneic L A K cells, adherent or nonadherent, were capable of extending survival but did not offer cures.…”

“…Our laboratory has reported on the in vitro and in vivo efficacy of human recombinant Interleukin-2 (rIL-2) with various preparations of cells which have been nonspecifically activatedto kill tumor in the rat 9L tumor model [3,4]. We have also reported the long-term follow-up of patients with recurrent malignant brain tumors treated by the Denver Brain Tumor Research Group with nonspecifically activated killer cells in conjunction with rIL-2 [2].…”

“…We report a number of in vivo rat experiments which demonstrate the potential of using single source allogeneic CTL for tumor therapy [1,3]. Multiple administrations of immune cells are more effective in lysing tumor cells than is a single administration [1].…”

Genetic and Immunology of Brain Tumors

“…An adaptive immune response implies antigen recognition (Prasad et al, 2004). A variety of immunologically based strategies, including passive immunization and adoptive cellular immunotherapy (Fujimiya et al, 1999;Inoue et al, 1996;Kruse et al, 1990;Merchant et al, 1997;Plautz et al, 1997;Plautz et al, 1998) local and systemic delivery of biological response modifiers (Dranoff et al, 1993;Färkkilä et al, 1994;Jean et al, 1998;Jean et al, 2004;Lichtor et al, 1995;Ohno et al, 2009;Thompson et al, 1996;Yu et al; and vaccination with parental and genetically modified tumor cells (Dranoff et al, 1993;Jean et al, 1998;Lichtor et al, 1995;Thompson et al, 1996;Ohno et al, 2009;Yu et al; have been attempted.…”