Summary of study ST001235

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000828. The data can be accessed directly via it's Project DOI: 10.21228/M8NQ4J This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

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Study IDST001235
Study TitleMetabolic responses to PD1 immune-checkpoint blockade and association with therapeutic benefits - Part I
Study SummaryInhibition of immune-checkpoint targets including PD1 is clinically effective in a variety of cancers. However, only a subset of patients respond and complete response remains uncommon. Given the known role of metabolites in modulating immunity, we sought to understand how individual patients’ metabolic activities adapt to PD1 immune checkpoint blockade and how they associate with therapeutic benefits. To this end, we profiled metabolites in pre- and multiple on-treatment patient serum samples from three independent immunotherapy trials using hydrophilic interaction liquid chromatography coupled with either triple quadrupole MS multiple reaction monitoring or high resolution full scan MS detection. The study consisted of two Phase I trials (CA209-038, NCT01621490; CA209-009, NCT01358721) which included 78 patients with advanced melanoma and 91 patients with metastatic renal cell carcinoma (RCC) treated with nivolumab. To investigate the generalizability of our results, we also analyzed a large randomized Phase III trial (CheckMate 025, NCT01668784) with 743 RCC patients, among which 394 received nivolumab and 349 received everolimus.
Institute
Broad Institute of MIT and Harvard
Last NameClish
First NameClary
Address415 Main St, Cambridge, MA 02142
Emailclary@broadinstitute.org
Phone617-714-7654
Submit Date2019-08-08
Num Groups1
Total Subjects78
Num Males44
Num Females34
Raw Data AvailableYes
Raw Data File Type(s).cd,.cg, .xml, .bin, .stg
Analysis Type DetailLC-MS
Release Date2019-08-27
Release Version1
Clary Clish Clary Clish
https://dx.doi.org/10.21228/M8NQ4J
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:


Project:

Project ID:PR000828
Project DOI:doi: 10.21228/M8NQ4J
Project Title:Metabolomic adaptations and correlates of survival to immune checkpoint blockade
Project Type:Serum metabolomcs
Project Summary:To investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profiled serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identified serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with IDO/TDO inhibitors.
Institute:Broad Institute of MIT and Harvard
Department:Metabolomics Platform
Last Name:Clish
First Name:Clary
Address:415 Main Street, Cambridge, MA, 02142, USA
Email:clary@broadinstitute.org
Phone:617-714-7654
Funding Source:Conquer Cancer Foundation ASCO Career Development Award; Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (grant number: SU2C-AACR-DT22-17); the Dana-Farber/Harvard Cancer Center Kidney Cancer program; NCI's Cancer Target Discovery and Development (CTD2) Network (grant number: U01CA217848); Kidney SPORE P50CA101942-12; the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute; the BMS II-ON consortium; and the AACR KureIt Grant for Kidney Cancer.
Contributors:Haoxin Li, Kevin Bullock, Carino Gurjao, David Braun, Sachet Shukla, Dominick Bossé, Aly-Khan A. Lalani, Shuba Gopal, Chelsea Jin, Christine Horak, Megan Wind-Rotolo, Sabina Signoretti, David F. McDermott, Gordon J. Freeman, Eliezer M. Van Allen, Stuart L. Schreiber, F. Stephen Hodi, William R. Sellers, Levi A. Garraway, Clary Clish, Toni K. Choueiri, Marios Giannakis

Subject:

Subject ID:SU001303
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Time point OS_Censor (1 means the time is a censoring time and 0 means a failure time in OS)
SA088208CA209038-3-66_baselinebaseline -
SA088209CA209038-6-62_baselinebaseline -
SA088210CA209038-7-70_baselinebaseline -
SA088211CA209038-9-74_baselinebaseline -
SA088212CA209038-3-76_baselinebaseline -
SA088213CA209038-1-59_baselinebaseline -
SA088214CA209038-9-53_baselinebaseline -
SA088215CA209038-9-46_baselinebaseline -
SA088216CA209038-1-39_baselinebaseline -
SA088217CA209038-4-47_baselinebaseline -
SA088218CA209038-4-52_baselinebaseline -
SA088219CA209038-5-77_baselinebaseline -
SA088220CA209038-1-58_baselinebaseline -
SA088221CA209038-5-79_baselinebaseline -
SA088222CA209038-5-98_baselinebaseline -
SA088223CA209038-7-92_baselinebaseline -
SA088224CA209038-5-100_baselinebaseline -
SA088225CA209038-13-106_baselinebaseline -
SA088226CA209038-1-1_baselinebaseline -
SA088227CA209038-7-90_baselinebaseline -
SA088228CA209038-6-86_baselinebaseline -
SA088229CA209038-7-80_baselinebaseline -
SA088230CA209038-3-81_baselinebaseline -
SA088231CA209038-1-82_baselinebaseline -
SA088232CA209038-5-84_baselinebaseline -
SA088233CA209038-8-38_baselinebaseline -
SA088234CA209038-3-89_baselinebaseline -
SA088235CA209038-12-11_baselinebaseline -
SA088236CA209038-8-10_baselinebaseline -
SA088237CA209038-12-28_baselinebaseline -
SA088238CA209038-8-17_baselinebaseline -
SA088239CA209038-10-27_baselinebaseline -
SA088240CA209038-12-13_baselinebaseline -
SA088241CA209038-12-16_baselinebaseline -
SA088242CA209038-1-23_baselinebaseline -
SA088243CA209038-8-25_baselinebaseline -
SA088244CA209038-12-14_baselinebaseline -
SA088245CA209038-8-9_baselinebaseline -
SA088246CA209038-10-29_baselinebaseline -
SA088247CA209038-14-35_baselinebaseline -
SA088248CA209038-8-4_baselinebaseline -
SA088249CA209038-8-5_baselinebaseline -
SA088250CA209038-1-2_baselinebaseline -
SA088251CA209038-9-37_baselinebaseline -
SA088252CA209038-5-83_baselinebaseline 1
SA088253CA209038-8-3_baselinebaseline 1
SA088254CA209038-5-87_baselinebaseline 1
SA088255CA209038-6-104_baselinebaseline 1
SA088256CA209038-4-94_baselinebaseline 1
SA088257CA209038-3-101_baselinebaseline 1
SA088258CA209038-3-93_baselinebaseline 1
SA088259CA209038-6-102_baselinebaseline 1
SA088260CA209038-5-91_baselinebaseline 1
SA088261CA209038-7-103_baselinebaseline 1
SA088262CA209038-4-105_baselinebaseline 1
SA088263CA209038-4-108_baselinebaseline 1
SA088264CA209038-8-32_baselinebaseline 1
SA088265CA209038-9-54_baselinebaseline 1
SA088266CA209038-10-31_baselinebaseline 1
SA088267CA209038-10-30_baselinebaseline 1
SA088268CA209038-14-34_baselinebaseline 1
SA088269CA209038-1-51_baselinebaseline 1
SA088270CA209038-8-18_baselinebaseline 1
SA088271CA209038-12-44_baselinebaseline 1
SA088272CA209038-9-36_baselinebaseline 1
SA088273CA209038-8-48_baselinebaseline 1
SA088274CA209038-5-60_baselinebaseline 1
SA088275CA209038-3-49_baselinebaseline 1
SA088276CA209038-1-71_baselinebaseline 1
SA088277CA209038-1-73_baselinebaseline 1
SA088278CA209038-10-24_baselinebaseline 1
SA088279CA209038-6-63_baselinebaseline 1
SA088280CA209038-12-26_baselinebaseline 1
SA088281CA209038-6-69_baselinebaseline 1
SA088282CA209038-6-68_baselinebaseline 1
SA088283CA209038-6-64_baselinebaseline 1
SA088284CA209038-4-67_baselinebaseline 1
SA088285CA209038-9-46_week 4week 4 -
SA088286CA209038-4-47_week 4week 4 -
SA088287CA209038-7-70_week 4week 4 -
SA088288CA209038-9-37_week 4week 4 -
SA088289CA209038-14-35_week 4week 4 -
SA088290CA209038-5-98_week 4week 4 -
SA088291CA209038-5-84_week 4week 4 -
SA088292CA209038-8-38_week 4week 4 -
SA088293CA209038-1-59_week 4week 4 -
SA088294CA209038-3-89_week 4week 4 -
SA088295CA209038-5-100_week 4week 4 -
SA088296CA209038-6-86_week 4week 4 -
SA088297CA209038-6-62_week 4week 4 -
SA088298CA209038-7-90_week 4week 4 -
SA088299CA209038-4-52_week 4week 4 -
SA088300CA209038-1-58_week 4week 4 -
SA088301CA209038-7-92_week 4week 4 -
SA088302CA209038-8-17_week 4week 4 -
SA088303CA209038-8-9_week 4week 4 -
SA088304CA209038-8-10_week 4week 4 -
SA088305CA209038-12-11_week 4week 4 -
SA088306CA209038-8-5_week 4week 4 -
SA088307CA209038-8-4_week 4week 4 -
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Collection:

Collection ID:CO001297
Collection Summary:Serum was collected at the specified time-points by centrifugation at 4000g for 4 minutes at 25°C within 2 hours of collection. Samples were frozen immediately and stored at or below -20°C for up to two months followed by storage at -80°C.
Sample Type:Blood (serum)
Storage Conditions:Described in summary

Treatment:

Treatment ID:TR001318
Treatment Summary:Serum samples were obtained from 78 participants in the the nivolumab monotherapy arm of CA209-038 (NCT01621490), a multi-institutional, multiarm prospective trial investigating the pharmacodynamics of nivolumab in patients with unresectable or metastatic melanoma.
Treatment Protocol ID:NCT01621490

Sample Preparation:

Sampleprep ID:SP001311
Sampleprep Summary:Serum samples (10 µL) were extracted using 90 µL of 74.9:24.9:0.2 (v/v/v) acetonitrile/methanol/formic acid containing stable isotope-labeled internal standards (0.2 ng/µL valine-d8, Isotec; 0.2 ng/µL phenylalanine-d8, Cambridge Isotope Laboratories). The samples were centrifuged (10 min, 9000g, 4ºC) and the supernatants were transferred to autosampler vials with de-activated inserts (Waters). Factors: OS_Censor (1 means the time is a censoring time and 0 means a failure time in Overall Survival)

Combined analysis:

Analysis ID AN002053
Analysis type MS
Chromatography type HILIC
Chromatography system Agilent 1290 Infinity II
Column Waters Atlantis HILIC (150 x 2.1 mm)
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name Agilent 6495 QQQ
Ion Mode POSITIVE
Units Log10(Peak Area)

Chromatography:

Chromatography ID:CH001492
Chromatography Summary:Extracts (10 µL) were injected onto a 150 x 2.1 mm Atlantis HILIC column (Waters). The column was eluted isocratically at a flow rate of 250 µL/min with 5% mobile phase A (10 mM ammonium formate and 0.1% formic acid in water) for 1 minute followed by a linear gradient to 40% mobile phase B (acetonitrile with 0.1% formic acid) over 10 minutes
Instrument Name:Agilent 1290 Infinity II
Column Name:Waters Atlantis HILIC (150 x 2.1 mm)
Column Temperature:30
Flow Rate:250 µL/min
Solvent A:10 mM ammonium formate and 0.1% formic acid in water
Solvent B:acetonitrile with 0.1% formic acid
Chromatography Type:HILIC

MS:

MS ID:MS001905
Analysis ID:AN002053
Instrument Name:Agilent 6495 QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:MS data were acquired using multiple reaction monitoring. Retention times, mass transitions, and collision energies were determined using authentic reference standards. Other MS parameters were: ion spray voltage, 3.0 kV; source temperature, 200°C; nozzle voltage, 500 V; gas flow, 14 L/min; nebulizer, 40 psi; sheath gas, 250°C; sheath gas flow, 1 L/min; iFunnel high pressure RF, 90; and low pressure RF, 90. Raw data were processed using MassHunter software (Agilent, Santa Clara, CA) for automated peak integration. The peak areas of 106 targeted metabolites were manually reviewed for quality of integration and compared against standard reference standards to confirm identities.
Ion Mode:POSITIVE
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