8 research outputs found
Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial
BackgroundThe gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. MethodsIn this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (& GE; 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (& GE; 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade & GE; 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. DiscussionTransplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness.Cellular mechanisms in basic and clinical gastroenterology and hepatolog
Interstellar MHD Turbulence and Star Formation
This chapter reviews the nature of turbulence in the Galactic interstellar
medium (ISM) and its connections to the star formation (SF) process. The ISM is
turbulent, magnetized, self-gravitating, and is subject to heating and cooling
processes that control its thermodynamic behavior. The turbulence in the warm
and hot ionized components of the ISM appears to be trans- or subsonic, and
thus to behave nearly incompressibly. However, the neutral warm and cold
components are highly compressible, as a consequence of both thermal
instability in the atomic gas and of moderately-to-strongly supersonic motions
in the roughly isothermal cold atomic and molecular components. Within this
context, we discuss: i) the production and statistical distribution of
turbulent density fluctuations in both isothermal and polytropic media; ii) the
nature of the clumps produced by thermal instability, noting that, contrary to
classical ideas, they in general accrete mass from their environment; iii) the
density-magnetic field correlation (or lack thereof) in turbulent density
fluctuations, as a consequence of the superposition of the different wave modes
in the turbulent flow; iv) the evolution of the mass-to-magnetic flux ratio
(MFR) in density fluctuations as they are built up by dynamic compressions; v)
the formation of cold, dense clouds aided by thermal instability; vi) the
expectation that star-forming molecular clouds are likely to be undergoing
global gravitational contraction, rather than being near equilibrium, and vii)
the regulation of the star formation rate (SFR) in such gravitationally
contracting clouds by stellar feedback which, rather than keeping the clouds
from collapsing, evaporates and diperses them while they collapse.Comment: 43 pages. Invited chapter for the book "Magnetic Fields in Diffuse
Media", edited by Elisabete de Gouveia dal Pino and Alex Lazarian. Revised as
per referee's recommendation
Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial
BackgroundThe gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. MethodsIn this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (& GE; 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (& GE; 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade & GE; 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. DiscussionTransplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness