Current State of Immune-Based Therapies for Glioblastoma

Lim, Michael; Weller, Michael; Chiocca, E. Antonio

doi:10.14694/edbk_159084

Cited by 13 publications

(4 citation statements)

References 37 publications

(39 reference statements)

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“…However, despite some promising pre-clinical results (5, 133,134), early studies with pD1, pDL1 or cTLA4 inhibitors against GBM have, at least as monotherapy, not yet fulfilled this promise (120,(135)(136)(137)(138)(139). Grossauer et al noted that neither cTLA4 inhibition nor pD1 inhibition increased efficacy against GBM when used as monotherapy (120).…”

Section: Immune Checkpoint Inhibitors: Monotherapymentioning

confidence: 99%

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

Sordillo

Helson

2017

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Section: Immune Checkpoint Inhibitors: Monotherapymentioning

confidence: 99%

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

Sordillo

Helson

2017

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“…Advances in immunology have led to development of promising therapies for treatment of glioma [1, 2]. However, at present, the median survival time from diagnosis of the most common adult type of glioma, glioblastoma, is only 14 months [3].…”

Section: Introductionmentioning

confidence: 99%

A nested case-control study of 277 prediagnostic serum cytokines and glioma

et al. 2017

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Recent research shows bidirectional communication between the normal brain and the peripheral immune system. Glioma is a primary brain tumor characterized by systemic immunosuppression. To better understand gliomagenesis, we evaluated associations between 277 prediagnostic serum cytokines and glioma. We used glioma (n = 487) and matched control (n = 487) specimens from the Janus Serum Bank Cohort in Oslo, Norway. Conditional logistic regression allowed us to identify those cytokines that were individually associated with glioma. Next, we used heat maps to compare case to control Pearson correlation matrices of 12 cytokines modeled in an in silico study of the interaction between the microenvironment and the tumor. We did the same for case-control correlation matrices of lasso-selected cytokines and all 277 cytokines in the data set. Cytokines related to glioma risk (P ≤ .05) more than 10 years before diagnosis are sIL10RB, VEGF, beta-Catenin and CCL22. LIF was associated with decreased glioma risk within five years before glioma diagnosis (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23, 0.94). After adjustment for cytokines above, the previously observed interaction between IL4 and sIL4RA persisted (> 20 years before diagnosis, OR = 1.72, 95% CI = 1.20, 2.47). In addition, during this period, case correlations among 12 cytokines were weaker than were those among controls. This pattern was also observed among 30 lasso- selected cytokines and all 277 cytokines. We identified four cytokines and one interaction term that were independently related to glioma risk. We have documented prediagnostic changes in serum cytokine levels that may reflect the presence of a preclinical tumor.

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“… 22 , 27 , 28 However, these therapies have not yet successfully been translated into the clinical setting. 29 …”

Section: Discussionmentioning

confidence: 99%

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma

et al. 2021

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Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan–Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone ( P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ ( P < .0001) and CD8+ IFN-γ ( P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain ( P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.

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Current State of Immune-Based Therapies for Glioblastoma

Cited by 13 publications

References 37 publications

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

A nested case-control study of 277 prediagnostic serum cytokines and glioma

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma

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