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Intravenously Infused Stem Cells for Cancer Treatment.

ABSTRACT: Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells.

SUBMITTER: Mercer-Smith AR

PROVIDER: S-EPMC8602714 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Intravenously Infused Stem Cells for Cancer Treatment.

Mercer-Smith Alison R AR Findlay Ingrid A IA Bomba Hunter N HN Hingtgen Shawn D SD

Stem cell reviews and reports 20210617 6

Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be ...[more]

PMID: 34138421

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Project description:Background and objectivesIntestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson's disease. The primary objectives of this trial were to investigate if continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady state plasma concentrations of levodopa that are equivalent in magnitude, and non-inferior in variability, to those obtained with LCIG in patients with advanced Parkinson's disease.MethodsA concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved intestinal levodopa/carbidopa gel (LCIG) in a randomized, 3-period cross-over, open-label multicenter trial. Formulations were infused for 16h to patients with Parkinson's disease who were using LCIG as their regular treatment. Patients were recruited at several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and non-inferior variability of DIZ101 and DIZ102 versus LCIG with respect to levodopa plasma concentrations.ResultsWith dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits when compared to LCIG in the 18 participants that received all treatments. While the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Due to poor uptake with LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n=20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient.DiscussionIt is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa containing solution.Trial registration informationClinicalTrials.gov Identifier: NCT03419806. Registration first posted 5 Feb 2018, first patient enrolled 16 Feb 2018. Link to registration.

Project description:Acute high-dose radiation injury damages the bone marrow hematopoietic stem and progenitor cell compartment. This damage compromises the functional ability of the bone marrow to produce mature blood cells and results in an increased risk of death due to hematopoietic complications. Past work has shown that the bone marrow endothelium provides critical cues, which promote hematopoietic stem cell regeneration after injury. Additionally, transfusion of endothelial cells after radiation injury has been shown to promote recovery of both the bone marrow vasculature and hematopoietic systems. In this work, we examined the regenerative capacity of intravenous infusion of umbilical cord-blood derived endothelial progenitor cells (EPCs) since this is a cell source which is easy to obtain, expand and cryopreserve. We show that pre-treatment with the Wnt-antagonist Dickkopf1 (Dkk1) augments EPC regenerative function in an allogeneic mouse transplant model. Here, hematopoietic recovery was assessed in Balb/c mice after 5 Gy total-body irradiation and transplantation with C57/BL6-derived EPCs either with or without Dkk1 pre-treatment. The Dkk1-treated EPC group had significantly faster recovery of peripheral white blood cells, total bone marrow cellularity, bone marrow progenitors and BM endothelial cells compared to EPC treatment alone or saline controls. Importantly, after an LD50/30 dose of 8 Gy in the Balb/c mouse, Dkk1-treated EPCs were able to rescue 100% of irradiated mice versus 80% in the EPC control group and only 33% in the saline-treated group. To understand how Dkk1 induces regenerative function in the EPCs, we screened for pro-regenerative factors secreted by the EPC in response to Dkk1. Dkk1-treated EPCs were observed to secrete high levels of the anti-fibrotic protein follistatin as well as several proteins known to promote regeneration including EGF, VEGF and G-CSF. This work demonstrates the potential for Dkk1-treated EPCs as a rescue therapeutic for victims of acute radiation injury.

Dataset Information

Intravenously Infused Stem Cells for Cancer Treatment.

Publications

Intravenously Infused Stem Cells for Cancer Treatment.

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