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

Choi, John; Medikonda, Ravi; Saleh, Laura; Kim, Timothy; Pant, Ayush; Srivastava, Siddhartha; Kim, Young Hoon; Jackson, Christina; Tong, Luqing; Routkevitch, Denis; Jackson, Christopher M.; Mathios, Dimitrios; Zhao, Tianna; Cho, Hyerim; Brem, Henry; Lim, Michael

doi:10.1080/2162402x.2021.1956142

Cited by 30 publications

(24 citation statements)

References 37 publications

(49 reference statements)

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“…Thus, combination of PD-1 blockade and BTLA blockade is promising and attractive, with some potent signaling pathways by which BTLA and PD-1 inhibit activity of T cell remain to be further elucidated [ 249 , 250 ]. Preclinic model proved that anti-BTLA and anti-PD-1 immunotherapy mainly promotes the activation of CD4 + T cells, CD8 + T cells and the secretion of IFN-γ that correlates with favorable survival [ 251 ]. However, there is still a long way to go before this combination therapy could be applied clinically.…”

Section: Glioblastomamentioning

confidence: 99%

Glioma targeted therapy: insight into future of molecular approaches

et al. 2022

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Gliomas are the common type of brain tumors originating from glial cells. Epidemiologically, gliomas occur among all ages, more often seen in adults, which males are more susceptible than females. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), standard of care and prognosis of gliomas can be dramatically different. Generally, circumscribed gliomas are usually benign and recommended to early complete resection, with chemotherapy if necessary. Diffuse gliomas and other high-grade gliomas according to their molecule subtype are slightly intractable, with necessity of chemotherapy. However, for glioblastoma, feasible resection followed by radiotherapy plus temozolomide chemotherapy define the current standard of care. Here, we discuss novel feasible or potential targets for treatment of gliomas, especially IDH-wild type glioblastoma. Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failure due to complex regulatory network. There is ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor associated macrophage, dendritic cell vaccine, CAR-T), tumor microenvironment, and combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options.

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Section: Glioblastomamentioning

confidence: 99%

Glioma targeted therapy: insight into future of molecular approaches

et al. 2022

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“…In this study, we also investigated whether the pre-existing levels of T cell infiltration could affect the immunotherapeutic efficacy of HSPPC-96 vaccination, since they are widely recognized as indicators predicting patients’ response to immunotherapies, such as immune checkpoint blockade ( 11 , 66 , 67 ). However, we did not observe any correlation of T cell infiltration levels, in terms of CD8 + , CD4 + and PD-1 + cell densities, with clinical outcomes ( Figures 2A–C ).…”

Section: Discussionmentioning

confidence: 99%

Low MxA Expression Predicts Better Immunotherapeutic Outcomes in Glioblastoma Patients Receiving Heat Shock Protein Peptide Complex 96 Vaccination

Wang

Chi

et al. 2022

Front. Oncol.

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Heat shock protein peptide complex 96 (HSPPC-96) has been proven to be a safe and preliminarily effective therapeutic vaccine in treating newly diagnosed glioblastoma multiforme (GBM) (NCT02122822). However, the clinical outcomes were highly variable, rendering the discovery of outcome-predictive biomarkers essential for this immunotherapy. We utilized multidimensional immunofluorescence staining to detect CD4+ CD8+ and PD-1+ immune cell infiltration levels, MxA and gp96 protein expression in pre-vaccination GBM tissues of 19 patients receiving HSPPC-96 vaccination. We observed low MxA expression was associated with longer OS than high MxA expression (48 months vs. 20 months, p=0.038). Long-term survivors (LTS) exhibited significantly lower MxA expression than short-term survivors (STS) (p= 0.0328), and ROC curve analysis indicated MxA expression as a good indicator in distinguishing LTS and STS (AUC=0.7955, p=0.0318). However, we did not observe any significant impact of immune cell densities or gp96 expression on patient outcomes. Finally, we revealed the association of MxA expression with prognosis linked to a preexisting TCR clone (CDR3-2) but was independent of the peripheral tumor-specific immune response. Taken together, low MxA expression correlated with better survival in GBM patients receiving HSPPC-96 vaccination, indicating MxA as a potential biomarker for early recognition of responsive patients to this immunotherapy.Clinical Trial Registration: ClinicalTrials.gov (NCT02122822) http://www. chictr.org.cn/enindex.aspx (ChiCTR-ONC-13003309).

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“…In the blockade of BTLA, an increase in the proliferation and expansion of NY-ESO-1-specific CD8+ T-cells was observed, and an increased efficiency of the use of antibodies targeting BTLA in combination with anti-PD-1 and anti-Tim-3 in melanoma was shown [ 214 ]. In in vivo models of glioblastoma, an increase in median overall survival was observed with the combination of anti-BTLA and anti-PD-1 therapies [ 215 ]. The synergistic effect of this antibody combination in enhancing T-cell proliferation and cytokine production has been described in urothelial carcinoma [ 216 ].…”

Section: Immune Checkpoint Receptorsmentioning

confidence: 99%

The Features of Checkpoint Receptor—Ligand Interaction in Cancer and the Therapeutic Effectiveness of Their Inhibition

et al. 2022

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To date, certain problems have been identified in cancer immunotherapy using the inhibition of immune checkpoints (ICs). Despite the excellent effect of cancer therapy in some cases when blocking the PD-L1 (programmed death-ligand 1) ligand and the immune cell receptors PD-1 (programmed cell death protein 1) and CTLA4 (cytotoxic T-lymphocyte-associated protein 4) with antibodies, the proportion of patients responding to such therapy is still far from desirable. This situation has stimulated the exploration of additional receptors and ligands as targets for immunotherapy. In our article, based on the analysis of the available data, the TIM-3 (T-cell immunoglobulin and mucin domain-3), LAG-3 (lymphocyte-activation gene 3), TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains), VISTA (V-domain Ig suppressor of T-cell activation), and BTLA (B- and T-lymphocyte attenuator) receptors and their ligands are comprehensively considered. Data on the relationship between receptor expression and the clinical characteristics of tumors are presented and are analyzed together with the results of preclinical and clinical studies on the therapeutic efficacy of their blocking. Such a comprehensive analysis makes it possible to assess the prospects of receptors of this series as targets for anticancer therapy. The expression of the LAG-3 receptor shows the most unambiguous relationship with the clinical characteristics of cancer. Its inhibition is the most effective of the analyzed series in terms of the antitumor response. The expression of TIGIT and BTLA correlates well with clinical characteristics and demonstrates antitumor efficacy in preclinical and clinical studies, which indicates their high promise as targets for anticancer therapy. At the same time, the relationship of VISTA and TIM-3 expression with the clinical characteristics of the tumor is contradictory, and the results on the antitumor effectiveness of their inhibition are inconsistent.

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

Cited by 30 publications

References 37 publications

Glioma targeted therapy: insight into future of molecular approaches

Glioma targeted therapy: insight into future of molecular approaches

Low MxA Expression Predicts Better Immunotherapeutic Outcomes in Glioblastoma Patients Receiving Heat Shock Protein Peptide Complex 96 Vaccination

The Features of Checkpoint Receptor—Ligand Interaction in Cancer and the Therapeutic Effectiveness of Their Inhibition

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