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

Study ID	ST001235
Study Title	Metabolic responses to PD1 immune-checkpoint blockade and association with therapeutic benefits - Part I
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.
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	2019-08-08
Num Groups	1
Total Subjects	78
Num Males	44
Num Females	34
Raw Data Available	Yes
Raw Data File Type(s)	d
Analysis Type Detail	LC-MS
Release Date	2019-08-27
Release Version	1

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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:	SU001303
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)
SA088208	CA209038-3-66_baseline	baseline	-
SA088209	CA209038-6-62_baseline	baseline	-
SA088210	CA209038-7-70_baseline	baseline	-
SA088211	CA209038-9-74_baseline	baseline	-
SA088212	CA209038-3-76_baseline	baseline	-
SA088213	CA209038-1-59_baseline	baseline	-
SA088214	CA209038-9-53_baseline	baseline	-
SA088215	CA209038-9-46_baseline	baseline	-
SA088216	CA209038-1-39_baseline	baseline	-
SA088217	CA209038-4-47_baseline	baseline	-
SA088218	CA209038-4-52_baseline	baseline	-
SA088219	CA209038-5-77_baseline	baseline	-
SA088220	CA209038-1-58_baseline	baseline	-
SA088221	CA209038-5-79_baseline	baseline	-
SA088222	CA209038-5-98_baseline	baseline	-
SA088223	CA209038-7-92_baseline	baseline	-
SA088224	CA209038-5-100_baseline	baseline	-
SA088225	CA209038-13-106_baseline	baseline	-
SA088226	CA209038-1-1_baseline	baseline	-
SA088227	CA209038-7-90_baseline	baseline	-
SA088228	CA209038-6-86_baseline	baseline	-
SA088229	CA209038-7-80_baseline	baseline	-
SA088230	CA209038-3-81_baseline	baseline	-
SA088231	CA209038-1-82_baseline	baseline	-
SA088232	CA209038-5-84_baseline	baseline	-
SA088233	CA209038-8-38_baseline	baseline	-
SA088234	CA209038-3-89_baseline	baseline	-
SA088235	CA209038-12-11_baseline	baseline	-
SA088236	CA209038-8-10_baseline	baseline	-
SA088237	CA209038-12-28_baseline	baseline	-
SA088238	CA209038-8-17_baseline	baseline	-
SA088239	CA209038-10-27_baseline	baseline	-
SA088240	CA209038-12-13_baseline	baseline	-
SA088241	CA209038-12-16_baseline	baseline	-
SA088242	CA209038-1-23_baseline	baseline	-
SA088243	CA209038-8-25_baseline	baseline	-
SA088244	CA209038-12-14_baseline	baseline	-
SA088245	CA209038-8-9_baseline	baseline	-
SA088246	CA209038-10-29_baseline	baseline	-
SA088247	CA209038-14-35_baseline	baseline	-
SA088248	CA209038-8-4_baseline	baseline	-
SA088249	CA209038-8-5_baseline	baseline	-
SA088250	CA209038-1-2_baseline	baseline	-
SA088251	CA209038-9-37_baseline	baseline	-
SA088252	CA209038-5-83_baseline	baseline	1
SA088253	CA209038-8-3_baseline	baseline	1
SA088254	CA209038-5-87_baseline	baseline	1
SA088255	CA209038-6-104_baseline	baseline	1
SA088256	CA209038-4-94_baseline	baseline	1
SA088257	CA209038-3-101_baseline	baseline	1
SA088258	CA209038-3-93_baseline	baseline	1
SA088259	CA209038-6-102_baseline	baseline	1
SA088260	CA209038-5-91_baseline	baseline	1
SA088261	CA209038-7-103_baseline	baseline	1
SA088262	CA209038-4-105_baseline	baseline	1
SA088263	CA209038-4-108_baseline	baseline	1
SA088264	CA209038-8-32_baseline	baseline	1
SA088265	CA209038-9-54_baseline	baseline	1
SA088266	CA209038-10-31_baseline	baseline	1
SA088267	CA209038-10-30_baseline	baseline	1
SA088268	CA209038-14-34_baseline	baseline	1
SA088269	CA209038-1-51_baseline	baseline	1
SA088270	CA209038-8-18_baseline	baseline	1
SA088271	CA209038-12-44_baseline	baseline	1
SA088272	CA209038-9-36_baseline	baseline	1
SA088273	CA209038-8-48_baseline	baseline	1
SA088274	CA209038-5-60_baseline	baseline	1
SA088275	CA209038-3-49_baseline	baseline	1
SA088276	CA209038-1-71_baseline	baseline	1
SA088277	CA209038-1-73_baseline	baseline	1
SA088278	CA209038-10-24_baseline	baseline	1
SA088279	CA209038-6-63_baseline	baseline	1
SA088280	CA209038-12-26_baseline	baseline	1
SA088281	CA209038-6-69_baseline	baseline	1
SA088282	CA209038-6-68_baseline	baseline	1
SA088283	CA209038-6-64_baseline	baseline	1
SA088284	CA209038-4-67_baseline	baseline	1
SA088285	CA209038-9-46_week 4	week 4	-
SA088286	CA209038-4-47_week 4	week 4	-
SA088287	CA209038-7-70_week 4	week 4	-
SA088288	CA209038-9-37_week 4	week 4	-
SA088289	CA209038-14-35_week 4	week 4	-
SA088290	CA209038-5-98_week 4	week 4	-
SA088291	CA209038-5-84_week 4	week 4	-
SA088292	CA209038-8-38_week 4	week 4	-
SA088293	CA209038-1-59_week 4	week 4	-
SA088294	CA209038-3-89_week 4	week 4	-
SA088295	CA209038-5-100_week 4	week 4	-
SA088296	CA209038-6-86_week 4	week 4	-
SA088297	CA209038-6-62_week 4	week 4	-
SA088298	CA209038-7-90_week 4	week 4	-
SA088299	CA209038-4-52_week 4	week 4	-
SA088300	CA209038-1-58_week 4	week 4	-
SA088301	CA209038-7-92_week 4	week 4	-
SA088302	CA209038-8-17_week 4	week 4	-
SA088303	CA209038-8-9_week 4	week 4	-
SA088304	CA209038-8-10_week 4	week 4	-
SA088305	CA209038-12-11_week 4	week 4	-
SA088306	CA209038-8-5_week 4	week 4	-
SA088307	CA209038-8-4_week 4	week 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)

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 2.1mm)
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 2.1mm)
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:	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