A prospective pilot study was performed in order to assess the safety of treating recurrent malignant gliomas (MGs) with locally infused autologous tumor infiltrating lymphocytes (TILs) and recombinant interleukin-2 (rIL-2). Six patients were entered between June 27, 1994 and June 2, 1995 and followed until July 1, 1998. At surgery an Ommaya reservoir was placed for later infusion of TILs and rIL-2. Following surgery, autologous TILs were expanded in vitro in the presence of rIL-2 and infused on treatment days 1 and 14, with concurrent rIL-2 infusions performed three times each week for one month. Following completion of immunotherapy all patients were offered chemotherapy. Phenotypic analysis demonstrated TILs to be T-lymphocytes (87-99% CD3+). Of these, 4 of 6 cases (67%) phenotyped as cytotoxic/suppressor T-lymphocytes (CD8+) and 2 of 6 cases (33%) phenotyped as helper/inducer T-lymphocytes (CD4+). TILs demonstrated limited selective cytotoxicity, with dose dependent cytotoxicity against autologous tumor, allogenic tumor and long term MG cell lines. There were no significant (Grade 3 or 4) complications. One patient developed transient low grade fevers, and 2 developed asymptomatic hydrocephalus. All patients developed transient and asymptomatic cerebral swelling, noted on the immediate post-treatment imaging studies. At three and six month follow-up, 3 patients responded with partial response, 2 demonstrated stable disease and 1 patient progressed. At long term follow-up, 1 patient had a complete response (45 month follow-up), 2 had a partial response (48 and 47 month follow-up) and 3 patients expired as a result of progressive disease (at 12, 12 and 18 months following immunotherapy). A relationship between subsequent chemotherapy or extent of resection to outcome was not apparent but could not be excluded. This pilot study demonstrated that locally infused autologous TILs and rIL-2 could be delivered without serious toxicity. Further studies are indicated to determine the safety and long term efficacy of TIL immunotherapy.
Infection is a major cause of morbidity following multiple traumatic and head injury. Although immunosuppression has been demonstrated after multiple traumatic injury, the effects of head injury on immune function have not been thoroughly investigated. In a prospective study of 10 severely head-injured patients, in vitro and in vivo parameters of cellular immune activity were assessed. In vitro measurements of lymphocyte surface antigen expression following mitogen stimulation were made serially over a 3-week period in 10 patients with severe head injury. The control group consisted of 20 healthy subjects. Phenotyping of peripheral blood lymphocytes (PBLs) was performed following incubation with and without mitogens. Phenotypes were determined by flow cytometry using monoclonal antibodies (MABs) to T lymphocyte subsets and the alpha subunit of interleukin 2 (IL-2) receptors. In vivo cellular immune function was determined by measuring patient responses to delayed-type hypersensitivity (DTH) skin testing within 24 h of injury. When head-injured patients were compared to controls, PBLs incubated in the presence of phytohemagglutinin (PHA) demonstrated a decrease in cells marking as T cells (p = 0.005), helper-inducer T cells (p = 0.001), and in the number of IL-2 receptor-bearing cells (p = 0.001). The functional ability of these lymphocyte subpopulations to proliferate in the presence of PHA was significantly suppressed within 24 h of injury and normalized within 3 weeks of injury. DTH skin testing to Candida, mumps, trichophyton, and PPD antigens was performed within 24 h of injury and resulted in anergic responses in all 10 patients when measured at 24, 48, and 72 h following administration. The overall infection rate was 60%, with the majority of infections occurring within the first 4 days following injury. The results of this study indicate that severe head injury results in suppression of cellular immune function with a corresponding high rate of infection. The possible significance of the decrease in the percentage of helper-inducer T cells and in the number of cells bearing IL-2 receptors following mitogen stimulation is discussed.
Infection is a major complication of severe head injury, occurring in 50% to 75% of patients who survive to hospitalization. Previous investigations of immune activity following head injury have demonstrated suppression of helper T-cell activation. In this study, the in vitro production of interferon-gamma (INF-gamma), interleukin-1 (IL-1), and interleukin-2 (IL-2) was determined in 25 head-injured patients following incubation of peripheral blood lymphocytes (PBL's) with the lymphocyte mitogen phytohemagglutin (PHA). In order to elucidate the functional status of cellular cytotoxicity, lymphokine-activated killer (LAK) cell cytotoxicity assays were performed both prior to and following incubation of PBL's with IL-2 in five patients with severe head injury. The production of INF-gamma and IL-2 by PHA-stimulated PBL's was maximally depressed within 24 hours of injury (p less than 0.001 for INF-gamma, p = 0.035 for IL-2) and partially normalized within 21 days of injury. There was no change in the production of IL-1. When comparing the in vitro LAK cell cytotoxicity of PBL's from head-injured patients and normal subjects, there was a significant depression in LAK cell cytotoxicity both prior to (p = 0.010) and following (p less than 0.001) incubation of PBL's with IL-2. The results of this study indicate that IL-2 and INF-gamma production, normally required for inducing cell-mediated immunity, is suppressed following severe head injury. The failure of IL-2 to enhance LAK cell cytotoxicity suggest that factors other than decreased IL-2 production, such as inhibitory soluble mediators or suppressor lymphocytes, may be responsible for the reduction in cellular immune activity following severe head injury. These findings may have significant implications in designing clinical studies aimed at reducing the incidence of infection following severe head injury.
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