A mechanistic perspective, clinical applications, and phage-display-assisted discovery of TNFα inhibitors

Alizadeh, Ali; Morris, Mitchell; Church, W. Bret; Yaqoubi, Shadi; Dastmalchi, Siavoush

doi:10.1016/j.drudis.2021.09.024

Cited by 3 publications

(1 citation statement)

References 98 publications

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“…With the advent of phage display systems (53,54) a wide range of macromolecular ligands may be fused to the lytic phage capsid allowing for targeted delivery of therapeutic payloads (52,55). This technology has been applied in the design of diverse therapeutic agents (56)(57)(58)(59)(60) and against a range of clinical objectives (60)(61)(62)(63)(64). It is especially useful in the field of cancer biology, in which many delivery systems are challenged by imprecise targeting and poor penetration into the tumor interstitium (65)(66)(67)(68).…”

Section: Introductionmentioning

confidence: 99%

EGFR-targeted bacteriophage lambda penetrates model stromal and colorectal carcinoma tissues, is taken up into carcinoma cells, and interferes with 3-dimensional tumor formation

et al. 2022

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IntroductionColorectal cancer and other adult solid cancers pose a significant challenge for successful treatment because the tumor microenvironment both hinders the action of conventional therapeutics and suppresses the immune activities of infiltrating leukocytes. The immune suppression is largely the effect of enhanced local mediators such as purine nucleosides and eicosanoids. Genetic approaches have the promise of interfering with these mechanisms of local immunosuppression to allow both intrinsic and therapeutic immunological anticancer processes. Bacterial phages offer a novel means of enabling access into tissues for therapeutic genetic manipulations.MethodsWe generated spheroids of fibroblastic and CRC cancer cells to model the 3-dimensional stromal and parenchymal components of colorectal tumours. We used these to examine the access and effects of both wildtype (WT) and epidermal growth factor (EGF)-presenting bacteriophage λ (WT- λ and EGF-λ) as a means of delivery of targeted genetic interventions in solid cancers. We used both confocal microscopy of spheroids exposed to AF488-tagged phages, and the recovery of viable phages as measured by plaque-forming assays to evaluate access; and measures of mitochondrial enzyme activity and cellular ATP to evaluate the outcome on the constituent cells.ResultsUsing flourescence-tagged derivatives of these bacteriophages (AF488-WT-λ and AF488-EGF-λ) we showed that phage entry into these tumour microenvironments was possible and that the EGF ligand enabled efficient and persistent uptake into the cancer cell mass. EGF-λ became localized in the intracellular portion of cancer cells and was subjected to subsequent cellular processing. The targeted λ phage had no independent effect upon mature tumour spheroids, but interfered with the early formation and growth of cancer tissues without the need for addition of a toxic payload, suggesting that it might have beneficial effects by itself in addition to any genetic intervention delivered to the tumour. Interference with spheroid formation persisted over the duration of culture.DiscussionWe conclude that targeted phage technology is a feasible strategy to facilitate delivery into colorectal cancer tumour tissue (and by extension other solid carcinomas) and provides an appropriate delivery vehicle for a gene therapeutic that can reduce local immunosuppression and/or deliver an additional direct anticancer activity.

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