Summary of study ST001237

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 IDST001237
Study TitleMetabolic responses to PD1 immune-checkpoint blockade and association with therapeutic benefits - Part III
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 Date2019-08-12
Num Groups1
Total Subjects743
Num Males552
Num Females191
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:SU001305
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) CRF_MSKCC_Risk_Group Treatment Prior antiangiogenic regimens (≥2)
SA089169CA209025-160-157_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089170CA209025-141-730_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089171CA209025-154-1019_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089172CA209025-1-1048_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089173CA209025-141-667_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089174CA209025-114-56_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089175CA209025-39-133_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089176CA209025-1-96_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089177CA209025-2-210_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089178CA209025-20-946_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089179CA209025-11-481_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089180CA209025-2-792_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089181CA209025-180-937_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089182CA209025-12-216_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089183CA209025-174-235_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089184CA209025-159-994_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089185CA209025-12-275_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089186CA209025-1-110_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089187CA209025-135-434_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089188CA209025-139-827_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089189CA209025-9-649_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089190CA209025-154-125_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089191CA209025-92-806_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089192CA209025-93-212_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089193CA209025-89-33_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089194CA209025-87-548_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089195CA209025-82-745_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089196CA209025-82-690_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089197CA209025-84-861_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089198CA209025-50-281_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089199CA209025-93-274_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089200CA209025-43-787_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089201CA209025-139-224_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089202CA209025-14-943_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089203CA209025-139-227_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089204CA209025-65-579_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089205CA209025-42-441_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089206CA209025-159-812_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089207CA209025-158-182_baselinebaseline 1 FAVORABLE EVEROLIMUS FALSE
SA089208CA209025-87-229_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089209CA209025-47-1037_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089210CA209025-86-735_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089211CA209025-158-77_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089212CA209025-44-464_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089213CA209025-139-775_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089214CA209025-103-747_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089215CA209025-1-1056_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089216CA209025-139-741_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089217CA209025-41-455_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089218CA209025-138-699_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089219CA209025-111-657_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089220CA209025-2-67_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089221CA209025-58-162_baselinebaseline 1 FAVORABLE EVEROLIMUS TRUE
SA089222CA209025-41-979_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089223CA209025-29-1002_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089224CA209025-39-147_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089225CA209025-97-765_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089226CA209025-43-248_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089227CA209025-65-329_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089228CA209025-9-892_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089229CA209025-90-105_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089230CA209025-89-174_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089231CA209025-9-756_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089232CA209025-89-725_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089233CA209025-82-338_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089234CA209025-75-112_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089235CA209025-44-643_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089236CA209025-43-941_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089237CA209025-6-586_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089238CA209025-72-394_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089239CA209025-73-511_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089240CA209025-43-743_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089241CA209025-174-1010_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089242CA209025-169-660_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089243CA209025-139-1006_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089244CA209025-17-1044_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089245CA209025-138-734_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089246CA209025-13-181_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089247CA209025-17-928_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089248CA209025-162-171_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089249CA209025-161-974_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089250CA209025-15-99_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089251CA209025-15-773_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089252CA209025-154-929_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089253CA209025-156-1017_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089254CA209025-161-577_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089255CA209025-24-840_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089256CA209025-118-255_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089257CA209025-170-221_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089258CA209025-101-142_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089259CA209025-22-1000_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089260CA209025-21-1039_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089261CA209025-21-849_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089262CA209025-23-8_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089263CA209025-173-757_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089264CA209025-18-954_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089265CA209025-2-10_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089266CA209025-21-1027_baselinebaseline 1 FAVORABLE NIVOLUMAB FALSE
SA089267CA209025-97-264_baselinebaseline 1 FAVORABLE NIVOLUMAB TRUE
SA089268CA209025-95-167_baselinebaseline 1 FAVORABLE NIVOLUMAB TRUE
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Collection:

Collection ID:CO001299
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:TR001320
Treatment Summary:CA209025 (CheckMate 025, NCT01668784) was a phase 3 study of nivolumab in comparison with everolimus for treatment of advanced renal cell carcinoma (RCC). The study was stratified according to region (United States or Canada, Western Europe, and the rest of the world), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk group, and the number of previous antiangiogenic therapy regimens (one or two) for advanced renal cell carcinoma. The MSKCC prognostic risk is based on the presence of zero (favorable risk), one (intermediate risk), or two or three (poor risk) of the following prognostic factors: anemia, hypercalcemia, and poor performance status. Nivolumab was administered at a dose of 3 mg per kilogram of body weight as a 60-minute intravenous infusion every 2 weeks and everolimus was administered orally as a daily dose of 10 mg.
Treatment Protocol ID:NCT01668784

Sample Preparation:

Sampleprep ID:SP001313
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 AN002055
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:CH001494
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:MS001907
Analysis ID:AN002055
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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