Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma

Akasaki, Yukio; Kikuchi, Tetsuro; Homma, Sadamu; Koido, Shigeo; Ohkusa, Toshifumi; Tasaki, Tetsunori; Hayashi, Kazumi; Komita, Hideo; Watanabe, Nobuyuki; Suzuki, Yuta; Yamamoto, Yohei; Mori, Ryosuke; Arai, Takao; Tanaka, Toshihide; Joki, Tatsuhiro; Yanagisawa, Takaaki; Murayama, Yuichi

doi:10.1007/s00262-016-1905-7

Cited by 55 publications

(49 citation statements)

References 24 publications

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“… 101) Some trails assessing the combination of TMZ chemotherapy with immunotherapies also showed enhanced anti-glioma effects in highly TMZ resistant cases. 102) Therefore, immunotherapy is also a promising new potential therapeutic strategy for GBM.…”

Section: Strategy For Enhancing Tmz Effectmentioning

confidence: 99%

“…Recently, immunotherapy with fusions of DCs and glioma cells (FC therapy) appears promising in GBM patients. In phase I/II trail, treating GBM patients with a combination of standard TMZ chemotherapy and DC-based vaccination significantly prolonged mOS and PFS, 102 – 105) as compared with the standard radio-chemotherapy treatments. 6) FC therapy helped the immune system recognize and eliminate the TMZ-induced chemo-resistant peptides, such as WT-1, gp100, and MAGE-A3.…”

Section: Strategy For Enhancing Tmz Effectmentioning

confidence: 99%

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Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

Jiapaer

Furuta

Tanaka

et al. 2018

Neurol. Med. Chir.(Tokyo)

273

211

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Glioblastoma (GBM) is a highly malignant type of primary brain tumor with a high mortality rate. Although the current standard therapy consists of surgery followed by radiation and temozolomide (TMZ), chemotherapy can extend patient’s post-operative survival but most cases eventually demonstrate resistance to TMZ. O6-methylguanine-DNA methyltransferase (MGMT) repairs the main cytotoxic lesion, as O6-methylguanine, generated by TMZ, can be the main mechanism of the drug resistance. In addition, mismatch repair and BER also contribute to TMZ resistance. TMZ treatment can induce self-protective autophagy, a mechanism by which tumor cells resist TMZ treatment. Emerging evidence also demonstrated that a small population of cells expressing stem cell markers, also identified as GBM stem cells (GSCs), contributes to drug resistance and tumor recurrence owing to their ability for self-renewal and invasion into neighboring tissue. Some molecules maintain stem cell properties. Other molecules or signaling pathways regulate stemness and influence MGMT activity, making these GCSs attractive therapeutic targets. Treatments targeting these molecules and pathways result in suppression of GSCs stemness and, in highly resistant cases, a decrease in MGMT activity. Recently, some novel therapeutic strategies, targeted molecules, immunotherapies, and microRNAs have provided new potential treatments for highly resistant GBM cases. In this review, we summarize the current knowledge of different resistance mechanisms, novel strategies for enhancing the effect of TMZ, and emerging therapeutic approaches to eliminate GSCs, all with the aim to produce a successful GBM treatment and discuss future directions for basic and clinical research to achieve this end.

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Section: Strategy For Enhancing Tmz Effectmentioning

confidence: 99%

Section: Strategy For Enhancing Tmz Effectmentioning

confidence: 99%

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

Jiapaer

Furuta

Tanaka

et al. 2018

Neurol. Med. Chir.(Tokyo)

273

211

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“…Further investigations are warranted to determine the adequate dosage and duration of anti-angiogenic agents for the combination usage with immune checkpoint inhibitors. Because immune checkpoint inhibitors and anti-VEGF/ VEGFR treatment are immunological "break off" strategies, other immunotherapies such as DCs-based immunotherapy [112], tumor vaccine therapy [113], and chimeric antigen receptor T-cell therapy [114] should be added to them as "acceleration on" strategies to improve therapeutic efficacy. Furthermore, hypoxia-targeted therapy is another treatment strategy to overcome the mechanisms of resistance to immunotherapy, via suppressing Tregs, TAMs, and MDSCs [115].…”

Section: Future Directionmentioning

confidence: 99%

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

et al. 2019

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The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological "cold tumors" into the "hot tumors". Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.

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“…Dalším směrem imunoterapie, která prokázala u selektované podskupiny pacientů s gliomy vysokého stupně malignity (high-grade glioma -HGG) a minimálním reziduem prodloužení přežívání, je protinádorová vakcinace na bázi autologních dendritických buněk [6,[12][13][14]. Akasaki et al prezentovali prodloužené přežívání pacientů s nově dia gnostikovaným GBM léčených kombinací TMZ a vakcinace dendritickými buňkami -přežití bez progrese 18,3 měsíce, celkové přežití 30,5 měsíce [15]. Naše pracoviště realizuje studii fáze I "Kombinovaná protinádorová terapie s autologní vakcínou z dendritických buněk produkujících interleukin 12 u dětských a adolescentních pacientů s progredujícími, relabujícími nebo primárně metastatickými malignitami vysokého rizika KDO_DC1311" (Eu-draCT number 2014-003388-39).…”

Section: Závěrunclassified

Effective Immunotherapy of Glioblastoma in an Adolescent with Constitutional Mismatch Repair-Deficiency Syndrome

Pavelka¹,

Zitterbart²,

Nosková³

et al. 2019

Klin Onkol

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Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma

Abstract: The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

Cited by 55 publications

References 24 publications

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

Effective Immunotherapy of Glioblastoma in an Adolescent with Constitutional Mismatch Repair-Deficiency Syndrome

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