Harnessing T-Cell Immunity to Target Brain Tumors

Walker, Paul R; Prins, Robert M.; Dietrich, Pierre‐Yves; Liau, Linda M.

doi:10.1007/978-1-60327-553-8_48

Cited by 4 publications

(5 citation statements)

References 179 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other current trials in patients with malignant glioma are evaluating irreversible EGFR inhibitors such as BIBW 2992 and PF‐00299804, the dual EGFR and VEGF receptor (VEGFR) inhibitor vandetanib (ZD6474), and the humanized monoclonal antibody against EGFR, nimotuzumab. CDX‐110, a peptide vaccine against the unique epitope of EGFRvIII, has a favorable toxicity profile and currently is being studied in combination with temozolomide in patients with newly diagnosed GBM 82. Finally, combinations of EGFR inhibitors with other targeted therapies, including inhibitors of mammalian target of rapamycin (mTOR) and VEGFR, are being evaluated (Table 1).…”

Section: Application Of Progress Made In Malignant Glioma Biology: Rementioning

confidence: 99%

“…This initial concept was later revised to accommodate the immunosurveillance that does occur in the brain and the powerful immune responses that take place in the infected brain or under conditions of autoimmune disease. The current concept is that immunoediting occurs and, in the case of CNS neoplasms, can result in various outcomes, namely cancer elimination, an equilibrium, and tumor immune escape 82. Malignant gliomas clearly represent a scenario in which the tumor has overcome the immune system and even co‐opts the leukocyte populations that invade the tumor.…”

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

“…The highly infiltrative nature of malignant gliomas makes T‐cell mediated immunity particularly attractive to track and destroy every disseminated tumor cell in the brain, while sparing the normal tissue 82. To elicit a potent T‐cell response, naïve T cells have to be exposed to the appropriate antigen in the lymph nodes.…”

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

“…The precise antigen‐presenting cell involved is unknown, but resident microglial cells in the brain subjected to further differentiation are possible candidates. The signals that permit extravasation of amplified antigen–stimulated effector T cells into the brain are becoming better understood 82. Because our knowledge regarding the best way to activate endogenous T‐cell responses against tumor antigens in the brain was initially limited, a widely used approach has been to perform adoptive immune transfer, that is, the local or systemic transfer of effector T cells after an in vitro priming process against a tumor antigen.…”

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

“…Novel approaches focus on eliciting an antitumor response directly in vivo, through direct injection of antigen (active immunotherapy or tumor vaccination) or by using DC‐based vaccines, in which DCs are pulsed with antigen in vitro and implanted intradermally in vivo to stimulate a wide spectrum of immune effector mechanisms. Phase 1 trials are currently ongoing in which patients receive autologous DCs that are pulsed with their own acid‐eluted tumor antigens; initial results have provided evidence of feasibility, safety, and bioactivity 82. Such approaches may lead to customized immunotherapy in the not‐so‐distant future, in which the patient's own immune system is boosted to produce antitumor responses.…”

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

See 4 more Smart Citations

Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma

Meir¹,

Hadjipanayis²,

Norden³

et al. 2010

CA: A Cancer Journal for Clinicians

1,199

953

View full text Add to dashboard Cite

Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensitymodulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.

show abstract

Section: Application Of Progress Made In Malignant Glioma Biology: Rementioning

confidence: 99%

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

Section: Toward Theragnostics Of Malignant Gliomas: Discovery Of Novementioning

confidence: 99%

See 3 more Smart Citations

Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma

Meir¹,

Hadjipanayis²,

Norden³

et al. 2010

CA: A Cancer Journal for Clinicians

1,199

953

View full text Add to dashboard Cite

show abstract

Immune Infiltration of Spontaneous Mouse Astrocytomas Is Dominated by Immunosuppressive Cells from Early Stages of Tumor Development

et al. 2010

Self Cite

View full text Add to dashboard Cite

Immune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V 12 HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-γ, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-γ) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies. Cancer Res; 70(12); 4829-39. ©2010 AACR.

show abstract

Unlocking Benzosampangine’s Potential: A Computational Approach to Investigating, Its Role as a PD-L1 Inhibitor in Tumor Immune Evasion via Molecular Docking, Dynamic Simulation, and ADMET Profiling

Ouchaoui,

Hadad,

Aherkou

et al. 2024

Bioinform Biol Insights

View full text Add to dashboard Cite

The interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1 plays a crucial role in tumor immune evasion, presenting a critical target for cancer immunotherapy. Despite being effective, current monoclonal antibodies present some drawbacks such as high costs, toxicity, and resistance development. Therefore, the development of small-molecule inhibitors is necessary, especially those derived from natural sources. In this study, benzosampangine is predicted as a promising PD-L1 inhibitor, with potential applications in cancer immunotherapy. Utilizing the high-resolution crystal structure of human PD-L1 (PDB ID: 5O45), we screened 511 natural compounds, identifying benzosampangine as a top candidate with exceptional inhibitory properties. Molecular docking predicted that benzosampangine exhibits a strong binding affinity for PD-L1 (−9.4 kcal/mol) compared with established controls such as CA-170 (−6.5 kcal/mol), BMS-202 (−8.6 kcal/mol), and pyrvinium (−8.9 kcal/mol). The compound’s predicted binding efficacy is highlighted by robust interactions with key amino acids (ILE54, TYR56, GLN66, MET115, ILE116, SER117, ALA121, ASP122) within the active site, notably forming 3 Pi-sulfur interactions with MET115—an interaction absents in control inhibitors. In addition, ADMET profiling suggests that over the control molecules, benzosampangine has several key advantages, including favorable solubility, permeability, metabolic stability, and low toxicity, while adhering to Lipinski’s rule of five. Molecular dynamic simulations predict the stability of the benzosampangine-PD-L1 complex, reinforcing its potential to sustain inhibition of the PD-1/PD-L1 pathway. MMGBSA analysis calculated a binding free energy (ΔGbind) of −39.39 kcal/mol for the benzosampangine-PD-L1 complex, with significant contributions from Coulombic, lipophilic, and Van der Waals interactions, validating the predicted docking results. This study investigates in silico benzosampangine, predicting its better molecular interactions and pharmacokinetic profile compared with several already known PD-L1 inhibitors.

show abstract

Harnessing T-Cell Immunity to Target Brain Tumors

Cited by 4 publications

References 179 publications

Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma

Exciting New Advances in Neuro-Oncology: The Avenue to a Cure for Malignant Glioma

Immune Infiltration of Spontaneous Mouse Astrocytomas Is Dominated by Immunosuppressive Cells from Early Stages of Tumor Development

Unlocking Benzosampangine’s Potential: A Computational Approach to Investigating, Its Role as a PD-L1 Inhibitor in Tumor Immune Evasion via Molecular Docking, Dynamic Simulation, and ADMET Profiling

Contact Info

Product

Resources

About