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Clinical translation of microbe-based therapies: Current clinical landscape and preclinical outlook.

ABSTRACT: Next generation microbe-based therapeutics, inspired by the success of fecal microbiota transplants, are being actively investigated in clinical trials to displace or eliminate pathogenic microbes to treat various diseases in the gastrointestinal tract, skin, and vagina. Genetically engineered microbes are also being investigated in the clinic as drug producing factories for biologic delivery, which can provide a constant local source of drugs. In either case, microbe-therapeutics have the opportunity to address unmet clinical needs and open new areas of research by reducing clinical side effects associated with current treatment modalities or by facilitating the delivery of biologics. This review will discuss examples of past and current clinical trials that are investigating microbe-therapeutics, both microbiome-modulating and drug-producing, for the treatment of a range of diseases. We then offer a perspective on how preclinical approaches, both those focused on developing advanced delivery systems and those that use in vitro microbiome model systems to inform formulation design, will lead to the realization of next-generation microbe-therapeutics.

SUBMITTER: Vargason AM

PROVIDER: S-EPMC6063871 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Clinical translation of microbe-based therapies: Current clinical landscape and preclinical outlook.

Vargason Ava M AM Anselmo Aaron C AC

Bioengineering & translational medicine 20180501 2

Next generation microbe-based therapeutics, inspired by the success of fecal microbiota transplants, are being actively investigated in clinical trials to displace or eliminate pathogenic microbes to treat various diseases in the gastrointestinal tract, skin, and vagina. Genetically engineered microbes are also being investigated in the clinic as drug producing factories for biologic delivery, which can provide a constant local source of drugs. In either case, microbe-therapeutics have the oppor ...[more]

PMID: 30065967

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Project description:ATRT is a highly aggressive and rare pediatric CNS tumor of very young children. Its genetic hallmark is bi-allelic inactivation of SMARCB1 encoding INI1. Rarely SMARCA4 encoding BRG1 is affected. Up to 30% are associated with constitutional heterozygous pathogenic variants in one of the two genes, giving rise to the Rhabdoid-Tumor-Predisposition-Syndromes (RTPS) 1 and 2. Characteristic DNA methylation profiles distinguish ATRT from other SMARCB1-deficient entities. Three distinct subtypes ATRT-MYC, -TYR, and -SHH are on record. ATRT-SHH may be further divided into the subgroups ATRT-SHH1A, -SHH1B, and -SHH2. The cure of ATRT remains challenging, notwithstanding an increasing understanding of molecular pathomechanisms and genetic background. The implementation of multimodal institutional treatment protocols has improved prognosis. Regardless of treatment approaches, clinical risk factors such as age, metastases, and DNA methylation subtype affect survival probability. We provide a critical appraisal of current conventional multimodal regimens and emerging targeted treatment approaches investigated in clinical trials and entity-specific registries. Intense treatment approaches featuring radiotherapy (RT) and high-dose chemotherapy (HDCT) face the difficulty of balancing tumor control and treatment-related toxicity. Current approaches focus on minimizing radiation fields by proton beam therapy or to withhold RT in HDCT-only approaches. Still, a 40-75% relapse rate upon first-line treatment reveals the need for novel treatment strategies in primary and even more in recurrent/refractory (r/r) disease. Among targeted treatments, immune checkpoint inhibitors and epigenetically active agents appear most promising. Success remains limited in single agent approaches. We hypothesize that mechanism-informed combination therapy will enhance response, as the low mutational burden of ATRT may contribute to acquiring resistance to single targeted agents. As DNA methylation group-specific gene expression profiles appear to influence response to distinct agents, the future treatment of ATRT should respect clinical and biological heterogeneity in risk group adjusted treatment protocols.

Dataset Information

Clinical translation of microbe-based therapies: Current clinical landscape and preclinical outlook.

Publications

Clinical translation of microbe-based therapies: Current clinical landscape and preclinical outlook.

Similar Datasets

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