Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention

O’Shea, Anne E.; Valdera, Franklin A.; Ensley, Daniel C.; Smolinsky, Todd R.; Cindass, Jessica L.; Bohan, Phillip M. Kemp; Hickerson, Annelies T.; Carpenter, Elizabeth L.; McCarthy, Patrick M.; Adams, Alexandra; Vreeland, Timothy J.; Clifton, Guy T.; Peoples, George E.

doi:10.1016/j.clim.2022.109095

Cited by 17 publications

(11 citation statements)

References 69 publications

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“…Although rapalogs are clinically approved for manifestations of TSC and certain cancers (Gomes et al., 2022 ; Martelli et al., 2018 ; O'Shea et al., 2022 ; Palavra et al., 2017 ), their wider impact on the tumour microenvironment has not been extensively examined. We found a trend of reduced EV secretion from TSC2 ‐deficient cells following rapamycin treatment, similar to that previously reported in murine cells (Kumar et al., 2021 ), combined with altered protein packaging into the EVs in vitro.…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Bhaoighill

Falcón‐Pérez

Royo

et al. 2023

J of Extracellular Vesicle

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Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2‐deficient and TSC2‐expressing cells and identified a distinct protein cargo in TSC2‐deficient EVs, containing an enrichment of proteins thought to be involved in tumour‐supporting signalling pathways. We show EVs from TSC2‐deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV‐associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.

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Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Bhaoighill

Falcón‐Pérez

Royo

et al. 2023

J of Extracellular Vesicle

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“…In fact, mTOR blockade during human Th1/Tc1 cell generation induced autophagy, which promoted the survival of an anti-apoptotic T cell population that possesses the capacity to persist in vivo for prolonged intervals 22 . Finally, if rapamycin effect on immune response is dose-dependent, a high exposure to rapamycin may cause also inhibition of mTORC2 with detrimental immunologic and metabolic consequences 23 . This may explain the better results obtained on several immunological parameters in the group treated with rapamycin 1 mg/m 2 /d.…”

Section: Discussionmentioning

confidence: 99%

Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis (RAP-ALS study)

Mandrioli

D’Amico

Zucchi

et al. 2023

Preprint

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In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells (Tregs), and autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Rapamycin has never been tested in ALS patients. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in Tregs from baseline to treatment end, was not attained. Of the secondary outcomes, rapamycin decreased mRNA relative expression of pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. Rapamycin, in combination with riluzole, was well tolerated and provided reassuring safety findings. Based on immunological effects, plasma concentration stability and safety, rapamycin 1 mg/m2/day resulted the best dosage in this study, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.

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“…The mTOR pathway is also integral to the immune response, and mTOR inhibitors were initially developed and continue to be used primarily as immunosuppressant agents. 17 mTOR inhibitors not only alter this pathway, but have been shown to decrease regulatory T-cell counts significantly during use. 18 Likely as a result of this immunosuppressive effect, some patients with VAs treated with sirolimus have developed serious infections.…”

Section: Introductionmentioning

confidence: 99%

“…Gain of function variants in this pathway can lead to overgrowth of veins, capillaries, and lymphatic vessels that constitute VAs. The mTOR pathway is also integral to the immune response, and mTOR inhibitors were initially developed and continue to be used primarily as immunosuppressant agents 17 . mTOR inhibitors not only alter this pathway, but have been shown to decrease regulatory T‐cell counts significantly during use 18 .…”

Section: Introductionmentioning

confidence: 99%

Infectious complications of vascular anomalies treated with sirolimus: A systematic review

Kalbfell,

Cohen‐Cutler,

Grisham

et al. 2023

Pediatric Blood & Cancer

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Background and objectivesInitially developed as immunosuppressive agents, mammalian target of rapamycin (mTOR) inhibitors are currently used widely in the management of vascular malformations and tumors. The incidence of infectious complications in the vascular anomalies (VA) population is not well defined. The goal of this systematic review was to better define the types and severity of reported infectious complications in patients with VAs treated with mTOR inhibition.MethodsThis was a systematic review conducted following PRISMA guidelines evaluating all research articles focused on infectious complications in patients with VAs treated with sirolimus or everolimus. Thirty articles including 1182 total patients and 316 infections (in 291 unique patients) were ultimately included.ResultsThe majority of infections were viral upper respiratory (n = 137, 54%), followed by pneumonia (n = 53, 20%), and cutaneous infections (n = 20, 8%). There were six total infection‐related fatalities, which all occurred in patients younger than 2 years. Two cases of Pneumocystis jirovecii pneumonia (PJP) were reported. These were infants with kaposiform hemangioendothelioma (KHE) who were also treated with steroids and did not receive PJP prophylaxis. Almost one‐third (n = 96, 32%) of infectious complications were graded 3–4 according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. Details of patient age, subtype of VA, and timing of infection were lacking from many reports.ConclusionsMost infectious complications reported in patients with VA on mTOR inhibitors were viral respiratory infections and non‐severe. Bacteremia, infectious fatalities, and PJP are exceedingly rare. Future studies are needed to clarify the spectrum of infectious risks in VA patients and to provide guidance for infection prevention.

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Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention

Cited by 17 publications

References 69 publications

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis (RAP-ALS study)

Infectious complications of vascular anomalies treated with sirolimus: A systematic review

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