Monitoring of Regulatory T Cell Frequencies and Expression of CTLA-4 on T Cells, before and after DC Vaccination, Can Predict Survival in GBM Patients

Fong, Brendan; Jin, Richard; Wang, Xiaoyan; Safaee, Michael; Lisiero, Dominique N.; Yang, Isaac; Li, Gang; Liau, Linda M.; Prins, Robert M.

doi:10.1371/journal.pone.0032614

Cited by 90 publications

(71 citation statements)

References 45 publications

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“…PI3K and Akt inhibitors selectively disrupt the homeostasis of Treg and result in a significant antitumor effect that is Treg-dependent. Recent clinical studies have correlated immune dysfunction after immunotherapy with an increase of Treg (48–50). The data presented in this report demonstrated that PI3K-Akt inhibition enhances antitumor immune responses when combined with vaccines by selectively reducing the number of Treg.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway

Eid

Samara

Ozbun

et al. 2014

Cancer Immunology Research

132

115

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Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses still are needed. The temporary nature of the therapy-induced immune response can be attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, T regulatory cells (Treg). Although the depletion of Treg has been shown to be effective in enhancing immune responses, selective depletion of these suppressive cells without affecting other immune cells has not been very successful, and new agents are sought. We found that PI3K-Akt pathway inhibitors selectively inhibit Treg with minimal effect on conventional T cells (Tconv). Our results clearly show selective in vitro inhibition of activation (as represented by a decrease in downstream signaling) and proliferation of Treg in comparison to Tconv when treated with different Akt and PI3K inhibitors. This effect has been observed in both human and murine CD4 T cells. In vivo treatment with these inhibitors resulted in a significant and selective reduction in Treg both in naïve and tumor-bearing mice. Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg-dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Treg. We show that these inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg-depletion.

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Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway

Eid

Samara

Ozbun

et al. 2014

Cancer Immunology Research

132

115

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“…These strategies were evaluated in early-phase clinical trials in newly-diagnosed GBM (111)(112)(113)(114). DC vaccine loaded with autologous tumor lysate was examined in a phase I clinical trial with 56 patients with relapsed GBM, resulting in a median PFS of 3 months and median OS of 9.6 months, with 2-year OS of 14.8% (115).…”

Section: Immunotherapy Of Gbmmentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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“…Previously, our group demonstrated that intracellular cytokine signaling (specifically that of STAT1 and STAT5 T cells) correlated with survival and also that regulatory T-cell population shifts were associated with clinical outcome (10, 11). …”

Section: Introductionmentioning

confidence: 99%

TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination

Hsu

Sedighim

Wang

et al. 2016

Cancer Immunology Research

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While immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next generation sequencing (NGS) approach to determine whether quantitative assessments of tumor infiltrating lymphocyte (TIL) content and the degree of overlap of T cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma (GBM) patients treated with autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy. A significant correlation was found between a higher estimated TIL content and increased time to progression (TTP) and overall survival (OS). In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response.

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Monitoring of Regulatory T Cell Frequencies and Expression of CTLA-4 on T Cells, before and after DC Vaccination, Can Predict Survival in GBM Patients

Cited by 90 publications

References 45 publications

Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway

Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination

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