Generation and testing of clinical-grade exosomes for pancreatic cancer

Mendt, Mayela Carolina; Kamerkar, Sushrut; Sugimoto, Hikaru; McAndrews, Kathleen M.; Wu, Chia Chin; Gagea, Mihai; Yang, Stephen C.; Blanko, Elena V.Rodriges; Peng, Qian; Ma, Xiaoyan; Marszalek, Joseph R.; Maitra, Anirban; Yee, Cassian; Rezvani, Katayoun; Shpall, Elizabeth J.; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1172/jci.insight.99263

Cited by 606 publications

(535 citation statements)

References 35 publications

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“…Current evidence for the hypoimmunogenic nature of MEX includes at least one study that investigated repeated doses of MEX in mice, which did not observe any overt toxicity according to hematologic and blood chemistry analyses, as well as in-depth histopathological evaluation of several different tissues. 40 Similarly, toxicity has not been observed with repeated dosing of exosomes derived from other fibroblasts and Hek293 cells. 40,41 However, further studies are required to validate that the apparent hypoimmunogenicity properties of MEX are reproducible across different disease models and dosing regimens.…”

Section: Mex Immunogenicitymentioning

confidence: 99%

“…40 Similarly, toxicity has not been observed with repeated dosing of exosomes derived from other fibroblasts and Hek293 cells. 40,41 However, further studies are required to validate that the apparent hypoimmunogenicity properties of MEX are reproducible across different disease models and dosing regimens.…”

Section: Mex Immunogenicitymentioning

confidence: 99%

“…Several studies have investigated the biodistribution patterns of fluorescently labeled MEX. 40,[44][45][46] Based on these published reports, systemically administered MEX appear to be cleared within a few hours and generally ultimately accumulate within the liver and spleen. However, these studies have largely focused on biodistribution associated with healthy, wild-type animals, which does not take into account the distinct underlying pathophysiology associated with individual diseases.…”

Section: Mex Biodistributionmentioning

confidence: 99%

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Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

et al. 2019

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Exosomes are nanovesicles secreted by virtually all cells. Exosomes mediate the horizontal transfer of various macromolecules previously believed to be cell-autonomous in nature, including nonsecretory proteins, various classes of RNA, metabolites, and lipid membrane-associated factors. Exosomes derived from mesenchymal stem/stromal cells (MSCs) appear to be particularly beneficial for enhancing recovery in various models of disease. To date, there have been more than 200 preclinical studies of exosome-based therapies in a number of different animal models. Despite a growing number of studies reporting the therapeutic properties of MSC-derived exosomes, their underlying mechanism of action, pharmacokinetics, and scalable manufacturing remain largely outstanding questions. Here, we review the global trends associated with preclinical development of MSC-derived exosome-based therapies, including immunogenicity, source of exosomes, isolation methods, biodistribution, and disease categories tested to date. Although the in vivo data assessing the therapeutic properties of MSC-exosomes published to date are promising, several outstanding questions remain to be answered that warrant further preclinical investigation.

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Section: Mex Immunogenicitymentioning

confidence: 99%

Section: Mex Immunogenicitymentioning

confidence: 99%

Section: Mex Biodistributionmentioning

confidence: 99%

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Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

et al. 2019

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“…Nonetheless, applications of cell-free biotherapeutics would benefit from exploring the directed modulation of molecular targets in recipient cells. For example, a recent clinical trial (NCT03608631) has engineered BM-MSC to produce EVs with shRNA against pancreatic cancer with KRAS G12D mutations 32 . In this study, CD47+ EVs were resistant to destruction by innate immunity and selectively internalized by pancreatic cancer cells in vivo; in return, improving overall survival rates.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the luminal and membrane-bound cargo of EVs remains distinct from the composition of the parent cells 29 ; thus, EV biogenesis and secretion is a highly regulated process which continues to be elucidated with technological advancements and multidisciplinary efforts 31 . As EV-based biotherapeutics are currently being tested in early human clinical trials 32 , it remains essential to further our basic understanding of EV biology while exploring diverse approaches for regenerative medicine 33 . Thus, the primary objectives of this study were 1) to provide novel insights towards proteomic cargo secreted by Panc-MSC in vitro and 2) assess the therapeutic potential of Panc-MSC EVs in vivo.…”

Section: Introductionmentioning

confidence: 99%

Ultrafiltration Segregates Tissue Regenerative Stimuli Harboured Within and Independent of Extracellular Vesicles

Cooper

Sherman

Dayarathna

et al. 2020

Preprint

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The release of extracellular vesicles (EV) from human multipotent stromal cells (MSC) has been proposed as a mechanism by which MSC mediate regenerative functions in vivo. Our recent work has characterized MSC derived from human pancreatic tissues (Panc-MSC) that generated a tissue regenerative secretome which could be used as an injectable biotherapeutic agent in vivo. Despite these advancements, it remains unknown whether tissue regenerative stimuli released by Panc-MSC are released independent or within extracellular vesicles (EVs).Herein, this study demonstrates ultrafiltration is a simple method to enrich for EVs which can be injected in murine models of blood vessel or pancreatic islet regeneration. The enrichment of EVs from Panc-MSC conditioned media (CM) was validated using nanoscale flow cytometry and atomic force microscopy; in addition to the exclusive detection of classical EV-markers CD9, CD81, CD63 using label-free mass spectrometry. Additionally, we identified several proregenerative stimuli, such as WNT5A or ANGPT1, exclusively detected in Panc-MSC EVenriched versus EV-depleted conditioned media. Human microvascular endothelial cell tubule formation was enhanced in response to both Panc-MSC CM fractions in vitro yet only intramuscular injection of EV-enriched CM demonstrated vascular regenerative functions in NOD/SCID mice with unilateral hind-limb ischemia (*

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Targeted Therapies for Pancreatic Cancer

Maitra

2023

The Pancreas

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Generation and testing of clinical-grade exosomes for pancreatic cancer

Cited by 606 publications

References 35 publications

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

Ultrafiltration Segregates Tissue Regenerative Stimuli Harboured Within and Independent of Extracellular Vesicles

Targeted Therapies for Pancreatic Cancer

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