Summary of study ST001236

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

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST001236
Study TitleMetabolic responses to PD1 immune-checkpoint blockade and association with therapeutic benefits - Part II
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. V600E is the most common BRAF mutation in melanoma and "BRAF_V600E" indicates the mutation status.
Institute
Broad Institute of MIT and Harvard
Last NameClish
First NameClary
Address415 Main St, Cambridge, MA 02142
Emailclary@broadinstitute.org
Phone617-714-7654
Submit Date2019-08-12
Num Groups1
Total Subjects91
Num Males61
Num Females30
Raw Data AvailableYes
Raw Data File Type(s).raw
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

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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:SU001304
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) Nivolumab Dose (mg/kg)
SA088459CA209009-11-8_baselinebaseline 1 0.3
SA088460CA209009-3-114_baselinebaseline 1 0.3
SA088461CA209009-14-59_baselinebaseline 1 0.3
SA088462CA209009-5-29_baselinebaseline 1 0.3
SA088463CA209009-2-102_baselinebaseline 1 0.3
SA088464CA209009-11-71_baselinebaseline 1 0.3
SA088465CA209009-9-47_baselinebaseline 1 0.3
SA088466CA209009-5-18_baselinebaseline 1 0.3
SA088467CA209009-4-54_baselinebaseline 1 0.3
SA088468CA209009-9-27_baselinebaseline 1 0.3
SA088469CA209009-1-43_baselinebaseline 1 10
SA088470CA209009-13-51_baselinebaseline 1 10
SA088471CA209009-15-94_baselinebaseline 1 10
SA088472CA209009-1-20_baselinebaseline 1 10
SA088473CA209009-11-57_baselinebaseline 1 10
SA088474CA209009-5-23_baselinebaseline 1 10
SA088475CA209009-15-81_baselinebaseline 1 10
SA088476CA209009-11-40_baselinebaseline 1 10
SA088477CA209009-14-107_baselinebaseline 1 10
SA088478CA209009-5-21_baselinebaseline 1 10
SA088479CA209009-1-62_baselinebaseline 1 10
SA088480CA209009-13-103_baselinebaseline 1 10
SA088481CA209009-13-111_baselinebaseline 1 10
SA088482CA209009-5-17_baselinebaseline 1 10
SA088483CA209009-5-3_baselinebaseline 1 10
SA088484CA209009-9-88_baselinebaseline 1 10
SA088485CA209009-9-119_baselinebaseline 1 10
SA088486CA209009-3-117_baselinebaseline 1 10
SA088487CA209009-5-41_baselinebaseline 1 10
SA088488CA209009-5-50_baselinebaseline 1 10
SA088489CA209009-11-38_baselinebaseline 1 10
SA088490CA209009-5-1_baselinebaseline 1 10
SA088491CA209009-9-45_baselinebaseline 1 10
SA088492CA209009-11-10_baselinebaseline 1 10
SA088493CA209009-9-52_baselinebaseline 1 10
SA088494CA209009-11-13_baselinebaseline 1 10
SA088495CA209009-5-28_baselinebaseline 1 10
SA088496CA209009-11-14_baselinebaseline 1 10
SA088497CA209009-11-11_baselinebaseline 1 10
SA088498CA209009-9-34_baselinebaseline 1 2
SA088499CA209009-5-63_baselinebaseline 1 2
SA088500CA209009-13-96_baselinebaseline 1 2
SA088501CA209009-11-56_baselinebaseline 1 2
SA088502CA209009-5-4_baselinebaseline 1 2
SA088503CA209009-8-100_baselinebaseline 1 2
SA088504CA209009-5-106_baselinebaseline 1 2
SA088505CA209009-2-48_baselinebaseline 1 2
SA088506CA209009-2-58_baselinebaseline 1 2
SA088507CA209009-14-87_baselinebaseline 1 2
SA088508CA209009-9-97_baselinebaseline 1 2
SA088509CA209009-12-115_baselinebaseline 1 2
SA088510CA209009-11-79_baselinebaseline 1 2
SA088420CA209009-9-74_baselinebaseline - 0.3
SA088421CA209009-13-90_baselinebaseline - 0.3
SA088422CA209009-4-68_baselinebaseline - 0.3
SA088423CA209009-6-39_baselinebaseline - 0.3
SA088424CA209009-5-2_baselinebaseline - 0.3
SA088425CA209009-14-80_baselinebaseline - 0.3
SA088426CA209009-2-84_baselinebaseline - 0.3
SA088427CA209009-14-98_baselinebaseline - 0.3
SA088428CA209009-2-42_baselinebaseline - 0.3
SA088429CA209009-15-77_baselinebaseline - 0.3
SA088430CA209009-1-118_baselinebaseline - 0.3
SA088431CA209009-15-83_baselinebaseline - 0.3
SA088432CA209009-9-30_baselinebaseline - 10
SA088433CA209009-8-105_baselinebaseline - 10
SA088434CA209009-10-112_baselinebaseline - 10
SA088435CA209009-15-76_baselinebaseline - 10
SA088436CA209009-11-12_baselinebaseline - 10
SA088437CA209009-5-6_baselinebaseline - 10
SA088438CA209009-14-69_baselinebaseline - 10
SA088439CA209009-11-93_baselinebaseline - 10
SA088440CA209009-11-25_baselinebaseline - 10
SA088441CA209009-11-24_baselinebaseline - 10
SA088442CA209009-11-5_baselinebaseline - 10
SA088443CA209009-13-36_baselinebaseline - 10
SA088444CA209009-3-15_baselinebaseline - 10
SA088445CA209009-4-49_baselinebaseline - 10
SA088446CA209009-1-86_baselinebaseline - 10
SA088447CA209009-2-64_baselinebaseline - 10
SA088448CA209009-1-32_baselinebaseline - 10
SA088449CA209009-1-72_baselinebaseline - 10
SA088450CA209009-9-66_baselinebaseline - 2
SA088451CA209009-4-95_baselinebaseline - 2
SA088452CA209009-6-99_baselinebaseline - 2
SA088453CA209009-3-26_baselinebaseline - 2
SA088454CA209009-14-89_baselinebaseline - 2
SA088455CA209009-2-85_baselinebaseline - 2
SA088456CA209009-15-75_baselinebaseline - 2
SA088457CA209009-5-22_baselinebaseline - 2
SA088458CA209009-5-73_baselinebaseline - 2
SA088545CA209009-9-47_week 4week 4 1 0.3
SA088546CA209009-11-71_week 4week 4 1 0.3
SA088547CA209009-11-8_week 4week 4 1 0.3
SA088548CA209009-3-114_week 4week 4 1 0.3
SA088549CA209009-5-18_week 4week 4 1 0.3
SA088550CA209009-9-27_week 4week 4 1 0.3
SA088551CA209009-2-102_week 4week 4 1 0.3
SA088552CA209009-14-59_week 4week 4 1 0.3
SA088553CA209009-5-29_week 4week 4 1 0.3
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Collection:

Collection ID:CO001298
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:TR001319
Treatment Summary:In CA209-009, NCT01358721, Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with metastatic renal cell carcinoma (mRCC).
Treatment Protocol ID:NCT01358721

Sample Preparation:

Sampleprep ID:SP001312
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).

Combined analysis:

Analysis ID AN002054
Analysis type MS
Chromatography type HILIC
Chromatography system Shimadzu Nexera X2
Column Waters Atlantis HILIC (150 x 2.1 mm)
MS Type ESI
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode POSITIVE
Units Log10(Peak Area)

Chromatography:

Chromatography ID:CH001493
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:Shimadzu Nexera X2
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:MS001906
Analysis ID:AN002054
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:High resolution, accurate mass data were acquired using a system comprised of a Shimadzu Nexera X2 U-HPLC (Shimadzu Corp.; Marlborough, MA) coupled to a Q Exactive hybrid quadrupole orbitrap mass spectrometer (Thermo Fisher Scientific; Waltham, MA). MS analyses were carried out using electrospray ionization in the positive ion mode using full scan analysis over 70-800 m/z at 70,000 resolution and 3 Hz data acquisition rate. Other MS settings were: sheath gas 40, sweep gas 2, spray voltage 3.5 kV, capillary temperature 350°C, S-lens RF 40, heater temperature 300°C, microscans 1, automatic gain control target 1e6, and maximum ion time 250 ms. Raw data were processed using TraceFinder software (Thermo Fisher Scientific; Waltham, MA) and Progenesis QI (Nonlinear Dynamics; Newcastle upon Tyne, UK). The identities of 202 profiled metabolites were confirmed using reference standards.
Ion Mode:POSITIVE
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