Modulation of T-cell function by gliomas

Roszman, Thomas L.; Elliott, Lucinda H.; Brooks, William H.

doi:10.1016/0167-5699(91)90068-5

Cited by 221 publications

(102 citation statements)

References 39 publications

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“…This approach is based on the observation that patients with malignant brain tumors are immunosuppressed, specifically for their T cell functions. 4 Gliomas are poor antigen presenting cells in vivo with low expression of MHC class I and II antigens. 5 They also secrete several immunosuppressive molecules such as TGF-␤2 and prostaglandin E 2 .…”

Section: Introductionmentioning

confidence: 99%

Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins

et al. 1998

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Section: Introductionmentioning

confidence: 99%

Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins

et al. 1998

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“…116 Also, long-term follow-up of glioma patients who received post-surgical intracavitary implantation of LAK cells and IL-2 showed no positive immunotherapeutic effects. 118 One of the likely explanations for this failure is a TGF-␤-mediated cellular immunosuppression observed in these patients, 119 manifested by a decreased PBL activity to mitogens and alloantigens and a decreased number of T cells. T cells isolated from these patients could not undergo clonal expansion after stimulation with mitogens.…”

Section: The Role Of Tgf-␤ In Tumor-induced Immunosuppressionmentioning

confidence: 99%

Effects of TGF-β on the immune system: implications for cancer immunotherapy

1999

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Transforming growth factor-␤ (TGF-␤) is a potent regulator of numerous processes including hematopoiesis, cell proliferation, differentiation and activation. TGF-␤ has pleiotropic and profound effects on the immune system and on hematologic malignancies, ie leukemia. It is the most potent immunosuppressor described to date. Evidence exists that the immunosuppressive potential of TGF-␤ is an important promoter of malignant cell growth. This is partly caused by TGF-␤-induced interference with the generation of tumor-specific cytotoxic T lymphocytes, but also by TGF-␤-induced promotion of angiogenesis and tumor stroma formation. Until now, significant clinical responses have not been achieved with the current cancer immunotherapeutic approaches. One of the possible explanations for this failure is immunosuppression induced by tumor-derived TGF-␤. Here, several strategies to counteract the immunosuppressive effects of TGF-␤ and the current limitations of these strategies will be discussed. Knowledge of the mechanisms by which TGF-␤ interferes with the development of an anti-tumor response and of the strategies to counteract these immunosuppressive activities is crucial to improve the current cancer immunotherapeutic approaches.

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“…Abnormal levels of TGFb, closely followed by immune suppression, reappear in patients before clinical signs of recurrence are detected by clinical or radiographic means. 17 We have previously demonstrated that TGF-b production by tumor cells may be blocked by antisense gene modification. 18 Using the aggressive rat GS tumor model 9L, we showed that GS cells modified in this manner were rendered more immunogenic than parental cells.…”

Section: Introductionmentioning

confidence: 99%

Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma

et al. 2006

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We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-b2 (TGF-b2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-b in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 Â 10 6 -2 Â 10 7 autologous tumor cells per injection. TGF-b2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-b antisense-modified tumor cells.

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Modulation of T-cell function by gliomas

Cited by 221 publications

References 39 publications

Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins

Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins

Effects of TGF-β on the immune system: implications for cancer immunotherapy

Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma

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