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.

Study ID	ST001236
Study Title	Metabolic responses to PD1 immune-checkpoint blockade and association with therapeutic benefits - Part II
Study Summary	Inhibition 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 Name	Clish
First Name	Clary
Address	415 Main St, Cambridge, MA 02142
Email	clary@broadinstitute.org
Phone	617-714-7654
Submit Date	2019-08-12
Num Groups	1
Total Subjects	91
Num Males	61
Num Females	30
Raw Data Available	Yes
Raw Data File Type(s)	raw(Thermo)
Analysis Type Detail	LC-MS
Release Date	2019-08-27
Release Version	1

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:	SU001304
Subject Type:	Human
Subject Species:	Homo sapiens
Taxonomy ID:	9606
Species Group:	Mammals

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)
SA088459	CA209009-11-8_baseline	baseline	1	0.3
SA088460	CA209009-3-114_baseline	baseline	1	0.3
SA088461	CA209009-14-59_baseline	baseline	1	0.3
SA088462	CA209009-5-29_baseline	baseline	1	0.3
SA088463	CA209009-2-102_baseline	baseline	1	0.3
SA088464	CA209009-11-71_baseline	baseline	1	0.3
SA088465	CA209009-9-47_baseline	baseline	1	0.3
SA088466	CA209009-5-18_baseline	baseline	1	0.3
SA088467	CA209009-4-54_baseline	baseline	1	0.3
SA088468	CA209009-9-27_baseline	baseline	1	0.3
SA088469	CA209009-1-43_baseline	baseline	1	10
SA088470	CA209009-13-51_baseline	baseline	1	10
SA088471	CA209009-15-94_baseline	baseline	1	10
SA088472	CA209009-1-20_baseline	baseline	1	10
SA088473	CA209009-11-57_baseline	baseline	1	10
SA088474	CA209009-5-23_baseline	baseline	1	10
SA088475	CA209009-15-81_baseline	baseline	1	10
SA088476	CA209009-11-40_baseline	baseline	1	10
SA088477	CA209009-14-107_baseline	baseline	1	10
SA088478	CA209009-5-21_baseline	baseline	1	10
SA088479	CA209009-1-62_baseline	baseline	1	10
SA088480	CA209009-13-103_baseline	baseline	1	10
SA088481	CA209009-13-111_baseline	baseline	1	10
SA088482	CA209009-5-17_baseline	baseline	1	10
SA088483	CA209009-5-3_baseline	baseline	1	10
SA088484	CA209009-9-88_baseline	baseline	1	10
SA088485	CA209009-9-119_baseline	baseline	1	10
SA088486	CA209009-3-117_baseline	baseline	1	10
SA088487	CA209009-5-41_baseline	baseline	1	10
SA088488	CA209009-5-50_baseline	baseline	1	10
SA088489	CA209009-11-38_baseline	baseline	1	10
SA088490	CA209009-5-1_baseline	baseline	1	10
SA088491	CA209009-9-45_baseline	baseline	1	10
SA088492	CA209009-11-10_baseline	baseline	1	10
SA088493	CA209009-9-52_baseline	baseline	1	10
SA088494	CA209009-11-13_baseline	baseline	1	10
SA088495	CA209009-5-28_baseline	baseline	1	10
SA088496	CA209009-11-14_baseline	baseline	1	10
SA088497	CA209009-11-11_baseline	baseline	1	10
SA088498	CA209009-9-34_baseline	baseline	1	2
SA088499	CA209009-5-63_baseline	baseline	1	2
SA088500	CA209009-13-96_baseline	baseline	1	2
SA088501	CA209009-11-56_baseline	baseline	1	2
SA088502	CA209009-5-4_baseline	baseline	1	2
SA088503	CA209009-8-100_baseline	baseline	1	2
SA088504	CA209009-5-106_baseline	baseline	1	2
SA088505	CA209009-2-48_baseline	baseline	1	2
SA088506	CA209009-2-58_baseline	baseline	1	2
SA088507	CA209009-14-87_baseline	baseline	1	2
SA088508	CA209009-9-97_baseline	baseline	1	2
SA088509	CA209009-12-115_baseline	baseline	1	2
SA088510	CA209009-11-79_baseline	baseline	1	2
SA088420	CA209009-9-74_baseline	baseline	-	0.3
SA088421	CA209009-13-90_baseline	baseline	-	0.3
SA088422	CA209009-4-68_baseline	baseline	-	0.3
SA088423	CA209009-6-39_baseline	baseline	-	0.3
SA088424	CA209009-5-2_baseline	baseline	-	0.3
SA088425	CA209009-14-80_baseline	baseline	-	0.3
SA088426	CA209009-2-84_baseline	baseline	-	0.3
SA088427	CA209009-14-98_baseline	baseline	-	0.3
SA088428	CA209009-2-42_baseline	baseline	-	0.3
SA088429	CA209009-15-77_baseline	baseline	-	0.3
SA088430	CA209009-1-118_baseline	baseline	-	0.3
SA088431	CA209009-15-83_baseline	baseline	-	0.3
SA088432	CA209009-9-30_baseline	baseline	-	10
SA088433	CA209009-8-105_baseline	baseline	-	10
SA088434	CA209009-10-112_baseline	baseline	-	10
SA088435	CA209009-15-76_baseline	baseline	-	10
SA088436	CA209009-11-12_baseline	baseline	-	10
SA088437	CA209009-5-6_baseline	baseline	-	10
SA088438	CA209009-14-69_baseline	baseline	-	10
SA088439	CA209009-11-93_baseline	baseline	-	10
SA088440	CA209009-11-25_baseline	baseline	-	10
SA088441	CA209009-11-24_baseline	baseline	-	10
SA088442	CA209009-11-5_baseline	baseline	-	10
SA088443	CA209009-13-36_baseline	baseline	-	10
SA088444	CA209009-3-15_baseline	baseline	-	10
SA088445	CA209009-4-49_baseline	baseline	-	10
SA088446	CA209009-1-86_baseline	baseline	-	10
SA088447	CA209009-2-64_baseline	baseline	-	10
SA088448	CA209009-1-32_baseline	baseline	-	10
SA088449	CA209009-1-72_baseline	baseline	-	10
SA088450	CA209009-9-66_baseline	baseline	-	2
SA088451	CA209009-4-95_baseline	baseline	-	2
SA088452	CA209009-6-99_baseline	baseline	-	2
SA088453	CA209009-3-26_baseline	baseline	-	2
SA088454	CA209009-14-89_baseline	baseline	-	2
SA088455	CA209009-2-85_baseline	baseline	-	2
SA088456	CA209009-15-75_baseline	baseline	-	2
SA088457	CA209009-5-22_baseline	baseline	-	2
SA088458	CA209009-5-73_baseline	baseline	-	2
SA088545	CA209009-9-47_week 4	week 4	1	0.3
SA088546	CA209009-11-71_week 4	week 4	1	0.3
SA088547	CA209009-11-8_week 4	week 4	1	0.3
SA088548	CA209009-3-114_week 4	week 4	1	0.3
SA088549	CA209009-5-18_week 4	week 4	1	0.3
SA088550	CA209009-9-27_week 4	week 4	1	0.3
SA088551	CA209009-2-102_week 4	week 4	1	0.3
SA088552	CA209009-14-59_week 4	week 4	1	0.3
SA088553	CA209009-5-29_week 4	week 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).

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 2.1mm)
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 2.1mm)
Column Temperature:	30
Flow Rate:	250 µL/min
Solvent A:	100% water; 0.1% formic acid; 10 mM ammonium formate
Solvent B:	100% acetonitrile; 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