Engineering challenges for brain tumor immunotherapy

Lyon, Johnathan G.; Mokarram, Nassir; Saxena, Tarun; Carroll, Sheridan L.; Bellamkonda, Ravi V.

doi:10.1016/j.addr.2017.06.006

Cited by 65 publications

(68 citation statements)

References 139 publications

(167 reference statements)

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“…This study demonstrates that it is possible to leverage endogenous mechanisms of scar formation to moderate tumor growth by modulating the behavior of cells other than those of the tumor. We have previously demonstrated similar containment by targeting brain tumor cells directly using a small cytostatic molecule, although that strategy is hindered by the typical constraints of drug delivery to the brain, often failing to deliver the therapeutic payload to the entire tumor mass . Here, we report the targeting of endogenous inflammatory mechanisms for the induced expressed of inhibitory matrix in the stromal space using the EPR effect via gold nanoparticles.…”

Section: Discussionmentioning

confidence: 95%

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth

Saxena

Lyon

Pai

et al. 2018

Adv Healthcare Materials

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Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically “walls‐off” the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall‐off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.

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Section: Discussionmentioning

confidence: 95%

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth

Saxena

Lyon

Pai

et al. 2018

Adv Healthcare Materials

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“…In addition to the BBB, there are other barriers that maintain the CNS as an immune-privileged system, including the blood-meningeal barriers and the blood-cerebrospinal fluid (CSF) barriers [141,142]. During homeostasis, these barriers do not allow entry of pathogens or blood-borne immune cells.…”

Section: Astrocytes As An Immune Regulator In the Tumor Microenvironmentmentioning

confidence: 99%

“…Currently, researchers are now looking for ways to modulate this therapy so it can be applied to more tumors, including tumors in the CNS [141]. Importantly, the effectiveness of strategies such as vaccine and immune checkpoint therapies rely on a strong response and presence of tumor infiltrating immune cells for antigen presentation, which is low in most brain tumors due to the limited presence of resident immune cells within the brain [141,181]. Some strategies to stimulate the immune response, such as adjuvants or tetanus and diphtheria boosters with vaccine administration have increased effectiveness [141,182,183].…”

Section: Cns Tumor Immunotherapies and Astrocytesmentioning

confidence: 99%

“…Importantly, the effectiveness of strategies such as vaccine and immune checkpoint therapies rely on a strong response and presence of tumor infiltrating immune cells for antigen presentation, which is low in most brain tumors due to the limited presence of resident immune cells within the brain [141,181]. Some strategies to stimulate the immune response, such as adjuvants or tetanus and diphtheria boosters with vaccine administration have increased effectiveness [141,182,183]. As discussed earlier, astrocytes play an important role in immunosuppression in the brain tumor microenvironment, however this function has not yet been targeted.…”

Section: Cns Tumor Immunotherapies and Astrocytesmentioning

confidence: 99%

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The Role of Astrocytes in Tumor Growth and Progression

Gronseth¹,

Wang²,

Harder³

et al. 2018

Astrocyte - Physiology and Pathology

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Current research is continually implicating the importance of astrocytes as active participants in neurological injury, disease, and tumor progression. This chapter will discuss some of these emerging concepts, especially as they relate to tumor biology. Astrocytes themselves can become tumorigenic, such as the case in gliomas, which often have aberrant signaling in key regulating genes of astrocyte development. Astrocytes secrete factors that maintain the tight junctions of the blood brain barrier (BBB), which in turn regulates the success or failure of metastatic cells extravasating into the brain. This astrocytic association with the brain vasculature also promotes brain tumor stem cell characteristics, which are known to be necessary for tumor initiation. Tumor cells within the brain make direct contacts with astrocytes through gap junctions, which subsequently lead to increased chemoresistance of the tumor cells. Astrocytes have also been shown to effect tumors cells via secretion of degradative enzymes, cytokines, chemokines, and growth factors, all of which have been shown to promote tumor cell proliferation, survival, and invasion. Thus, research in astrocyte biology and the role of astrocytes in the tumor microenvironment has and will likely continue to reveal novel targets for cancer intervention.

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“…Crossing the blood brain barrier remains a challenge for the treatment of glioblastoma and other malignant brain tumors [377].…”

Section: Future Perspectives: Characterizing Membrane Active Peptidesmentioning

confidence: 99%

Membrane Active Peptides and Their Biophysical Characterization

Avcı

Akbulut

Özkırımlı

2018

Preprint

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In the last 20 years, an increasing number of studies have been reported on membrane active peptides, which exert their biological activity by interacting with the cell membrane either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. These peptides are attractive alternatives to currently used pharmaceuticals. Antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery currently in the drug pipeline suggest that these membrane active peptides will soon constitute a significant percentage of the drug market. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). AMPs are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus and fungi. CPPs are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity to some extent. Biophysical techniques to understand how they interact with the membrane have shed light on the peptide-membrane interaction at various levels of detail. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Advances in live imaging techniques have allowed examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provided clues on the peptide-lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC.

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Engineering challenges for brain tumor immunotherapy

Cited by 65 publications

References 139 publications

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth

The Role of Astrocytes in Tumor Growth and Progression

Membrane Active Peptides and Their Biophysical Characterization

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