Transforming Growth Factor-β Inhibits Interferon-γ Secretion by Lymph okine-activated Killer Cells Stimulated with Tumor Cells

Naganuma, Hirofumi; Sasaki, Atsushi; Satoh, Eiji; Nagasaka, Mitsuyasu; Nakano, Shin; Isoe, Shiro; Tasaka, Kachio; Nukui, Hideaki

doi:10.2176/nmc.36.789

Cited by 44 publications

(24 citation statements)

References 27 publications

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“…Immune suppression mediated by TGF-b appears to be due to impairment of IL-2R function and suppression of high affinity IL-2R expression, 29 inhibition of natural killer cells (NK) and lymphokine-activated killer cells (LAK) induction and proliferation, 30,31 and the inhibition of maturation and antigen presentation of dendritic cells. 32,33 However, effector cells, once they become activated, are refractory to the immune inhibitory properties of TGF-b and are capable of targeting and destroying tumor cells that continue to secrete TGF-b.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…TGF-b2 also antagonizes natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and DC function (20,21,(31)(32)(33)(34). GVAX was shown to enhance tumor antigen expression and DC migration to the vaccination site (35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine

Olivares

Kumar

et al. 2011

Clinical Cancer Research

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Purpose: On the basis of the hypothesis that the combined expression of immunostimulatory granulocyte macrophage colony stimulating factor (GM-CSF) and antitumor suppressor TGF-b2 antisense (AS) transgenes can break tolerance and stimulate immune responses to cancer-associated antigens, we constructed an expression plasmid [the tumor-associated glycoprotein (TAG) plasmid] that coexpresses GM-CSF and TGF-b2 AS nucleotide sequences and which was incorporated into an autologous whole-cell vaccine.Experimental Design: Patients undergoing resection were enrolled. Freshly harvested autologous tumor cells were mechanically and enzymatically disaggregated, then electroporated with the TAG vector. The resulting vaccine was irradiated, then aliquoted and cryopreserved until the time of injection. Patients received a minimum of 5 to a maximum of 12 monthly intradermal injections. Immune function was monitored at baseline and at months 3 and 6.

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“…These cells through cytokines, growth factors, chemokines and cerebrospinal fluid (CSF) interfere with tumor initiation, angiogenesis, proliferation and invasion [29]. IL-1β is the primary factor of microglia that enhances TGF-β, that, in turn, inhibits lymphocyte proliferation by suppressing antiglioma responses [30]. IL-1β also stimulates VEGF, epidermal growth factor receptor (EGFR) and MMP9 for angiogenesis, proliferation and invasion [31].…”

Section: Molecular Considerations and Evolving Surgical Management Ismentioning

confidence: 99%

Tumor Microenvironment — Perivascular and Perinecrotic Niches

Schiffer¹,

Mellai²,

Annovazzi³

et al. 2015

Molecular Considerations and Evolving Surgical Management Issues in the Treatment of Patients With a Brain Tumor

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Transforming Growth Factor-β Inhibits Interferon-γ Secretion by Lymph okine-activated Killer Cells Stimulated with Tumor Cells

Cited by 44 publications

References 27 publications

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

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

Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine

Tumor Microenvironment — Perivascular and Perinecrotic Niches

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