Summary of Study ST002110

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 PR001336. The data can be accessed directly via it's Project DOI: 10.21228/M81D70 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	ST002110
Study Title	Towards a mechanistic understanding of patient response to neoadjuvant SBRT with anti-PDL1 in human HPV-unrelated locally advanced HNSCC: Phase I/Ib trial results (Part 2)
Study Summary	Five-year survival for HPV-unrelated head and neck squamous cell carcinomas (HNSCC) remains below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy (SBRT) with anti-PDL-1 neoadjuvantly followed by adjuvant anti-PDL-1 with standard of care therapy (n=21). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic, and objective response, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). Among evaluable patients at early median follow-up of 16 months (448 days), OS was 83.3%, LRC and PFS were 83.3%, and major pathological response (MPR) or complete response (CR) was 75%. Circulating CD8/Treg ratio, CD4 effector memory T cells, and TCR repertoire emerged as biologic correlates of response to therapy. Using high-dimensional multi-omics and spatial data as well as biological correlatives pre- and post-treatment, three major changes were noted in responders within the tumor microenvironment (TME) (and within the blood) post-treatment: 1) an increase in effector T cells; 2) a decrease in immunosuppressive cells; and 3) an increase in antigen presentation. Non-responders appeared to fail due to a lack of one of these three identified steps needed for priming and maintaining activation of T cells. Multiple correlates for response, along with subsets of non-responders that may benefit from additional or alternative immunotherapies, were identified. This treatment is being tested in an ongoing phase II trial with a similar design, where we hope to confirm and expand on our understanding of the mechanisms underlying resistance to therapy.
Institute	University of Colorado Denver
Last Name	Culp-Hill
First Name	Rachel
Address	12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA
Email	rachel.hill@cuanschutz.edu
Phone	303-724-5798
Submit Date	2022-03-09
Raw Data Available	Yes
Raw Data File Type(s)	mzXML
Analysis Type Detail	LC-MS
Release Date	2022-04-04
Release Version	1

Select appropriate tab below to view additional metadata details:

Project:

Project ID:	PR001336
Project DOI:	doi: 10.21228/M81D70
Project Title:	Towards a mechanistic understanding of patient response to neoadjuvant SBRT with anti-PDL1 in human HPV-unrelated locally advanced HNSCC: Phase I/Ib trial results
Project Summary:	Five-year survival for HPV-unrelated head and neck squamous cell carcinomas (HNSCC) remains below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy (SBRT) with anti-PDL-1 neoadjuvantly followed by adjuvant anti-PDL-1 with standard of care therapy (n=21). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic, and objective response, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). Among evaluable patients at early median follow-up of 16 months (448 days), OS was 83.3%, LRC and PFS were 83.3%, and major pathological response (MPR) or complete response (CR) was 75%. Circulating CD8/Treg ratio, CD4 effector memory T cells, and TCR repertoire emerged as biologic correlates of response to therapy. Using high-dimensional multi-omics and spatial data as well as biological correlatives pre- and post-treatment, three major changes were noted in responders within the tumor microenvironment (TME) (and within the blood) post-treatment: 1) an increase in effector T cells; 2) a decrease in immunosuppressive cells; and 3) an increase in antigen presentation. Non-responders appeared to fail due to a lack of one of these three identified steps needed for priming and maintaining activation of T cells. Multiple correlates for response, along with subsets of non-responders that may benefit from additional or alternative immunotherapies, were identified. This treatment is being tested in an ongoing phase II trial with a similar design, where we hope to confirm and expand on our understanding of the mechanisms underlying resistance to therapy.
Institute:	University of Colorado Denver
Last Name:	Culp-Hill
First Name:	Rachel
Address:	12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA
Email:	rachel.hill@cuanschutz.edu
Phone:	303-724-5798

Subject:

Subject ID:	SU002195
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	NA	Pre
SA202402	BW48-38	NA	Post
SA202403	BW48-39	NA	Post
SA202404	BW48-40	NA	Post
SA202405	BW48-37	NA	Pre
SA202406	BW48-36	NA	Pre
SA202433	BW48-1	non-responder	Post
SA202434	BW48-5	non-responder	Post
SA202435	BW48-29	non-responder	Post
SA202436	BW48-7	non-responder	Post
SA202437	BW48-25	non-responder	Post
SA202438	BW48-4	non-responder	Pre
SA202439	BW48-6	non-responder	Pre
SA202440	BW48-28	non-responder	Pre
SA202441	BW48-24	non-responder	Pre
SA202407	BW48-13	Responder	Post
SA202408	BW48-15	Responder	Post
SA202409	BW48-11	Responder	Post
SA202410	BW48-9	Responder	Post
SA202411	BW48-3	Responder	Post
SA202412	BW48-17	Responder	Post
SA202413	BW48-21	Responder	Post
SA202414	BW48-33	Responder	Post
SA202415	BW48-35	Responder	Post
SA202416	BW48-19	Responder	Post
SA202417	BW48-31	Responder	Post
SA202418	BW48-27	Responder	Post
SA202419	BW48-23	Responder	Post
SA202420	BW48-30	Responder	Pre
SA202421	BW48-32	Responder	Pre
SA202422	BW48-34	Responder	Pre
SA202423	BW48-26	Responder	Pre
SA202424	BW48-18	Responder	Pre
SA202425	BW48-8	Responder	Pre
SA202426	BW48-2	Responder	Pre
SA202427	BW48-22	Responder	Pre
SA202428	BW48-10	Responder	Pre
SA202429	BW48-12	Responder	Pre
SA202430	BW48-20	Responder	Pre
SA202431	BW48-16	Responder	Pre
SA202432	BW48-14	Responder	Pre

Showing results 1 to 40 of 40

Showing results 1 to 40 of 40

Collection:

Collection ID:	CO002188
Collection Summary:	This was a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible for treatment had to be diagnosed with non-metastatic, biopsy-proven p16-negative histology squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and had to be eligible and amenable to surgical resection. This study enrolled using a 3+3 model. Patients received one dose of neoadjuvant Durvalumab 1500 mg approximately 3-6 weeks before standard-of-care surgery given concurrently with the first dose of radiation (RT). The starting RT dose level was 6 Gy for 2 fractions (12 Gy total) every other day over approximately one week to sites of gross disease (Table 1) to minimize exposure to normal tissue. If toxicity developed and surgery was delayed by more than 6 weeks due to treatment toxicity (qualifying as a DLT), the radiation dose was set to be dropped per protocol for the next set of patients. If this dose was tolerated, the dose was increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients. Patients proceeded to surgical resection approximately 3-6 weeks after radiation as recommended by the ENT surgeon. Post-operatively, pathology was reviewed at the multi-disciplinary head and neck conference, and the need for adjuvant therapy was discussed. For the first 8 patients, all patients were given adjuvant therapy based on presenting features. However, after patient 8, adjuvant therapy was dictated based on high-risk pathologic features as per the NCCN guidelines and treating physician recommendations. Adjuvant radiation included intensity-modulated radiation therapy of 60 Gy in 2 Gy once-daily fraction size once-daily fraction size (total of 30 fractions). If indicated, adjuvant systemic therapy included cisplatin or other cytotoxic chemotherapy or targeted biologics (Cetuximab) per physician discretion. All patients received adjuvant durvalumab to be initiated approximately 6-12 weeks post-surgery. It was given as 1500 mg intravenously once every 4 weeks for a maximum of 6 doses, or until progression, toxicity, or withdrawal from study. This was delivered either as monotherapy or concurrently with adjuvant radiation +/- systemic therapy for high-risk patients. Safety and toxicity evaluations were done throughout the study process. DLTs and adjustment of radiation doses were done during the neoadjuvant period.
Sample Type:	Blood (plasma)

Treatment:

Treatment ID:	TR002207
Treatment Summary:	This was a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible for treatment had to be diagnosed with non-metastatic, biopsy-proven p16-negative histology squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and had to be eligible and amenable to surgical resection. This study enrolled using a 3+3 model. Patients received one dose of neoadjuvant Durvalumab 1500 mg approximately 3-6 weeks before standard-of-care surgery given concurrently with the first dose of radiation (RT). The starting RT dose level was 6 Gy for 2 fractions (12 Gy total) every other day over approximately one week to sites of gross disease (Table 1) to minimize exposure to normal tissue. If toxicity developed and surgery was delayed by more than 6 weeks due to treatment toxicity (qualifying as a DLT), the radiation dose was set to be dropped per protocol for the next set of patients. If this dose was tolerated, the dose was increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients. Patients proceeded to surgical resection approximately 3-6 weeks after radiation as recommended by the ENT surgeon. Post-operatively, pathology was reviewed at the multi-disciplinary head and neck conference, and the need for adjuvant therapy was discussed. For the first 8 patients, all patients were given adjuvant therapy based on presenting features. However, after patient 8, adjuvant therapy was dictated based on high-risk pathologic features as per the NCCN guidelines and treating physician recommendations. Adjuvant radiation included intensity-modulated radiation therapy of 60 Gy in 2 Gy once-daily fraction size once-daily fraction size (total of 30 fractions). If indicated, adjuvant systemic therapy included cisplatin or other cytotoxic chemotherapy or targeted biologics (Cetuximab) per physician discretion. All patients received adjuvant durvalumab to be initiated approximately 6-12 weeks post-surgery. It was given as 1500 mg intravenously once every 4 weeks for a maximum of 6 doses, or until progression, toxicity, or withdrawal from study. This was delivered either as monotherapy or concurrently with adjuvant radiation +/- systemic therapy for high-risk patients. Safety and toxicity evaluations were done throughout the study process. DLTs and adjustment of radiation doses were done during the neoadjuvant period.

Treatment ID:

TR002207

Treatment Summary:

This was a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible for treatment had to be diagnosed with non-metastatic, biopsy-proven p16-negative histology squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and had to be eligible and amenable to surgical resection. This study enrolled using a 3+3 model. Patients received one dose of neoadjuvant Durvalumab 1500 mg approximately 3-6 weeks before standard-of-care surgery given concurrently with the first dose of radiation (RT). The starting RT dose level was 6 Gy for 2 fractions (12 Gy total) every other day over approximately one week to sites of gross disease (Table 1) to minimize exposure to normal tissue. If toxicity developed and surgery was delayed by more than 6 weeks due to treatment toxicity (qualifying as a DLT), the radiation dose was set to be dropped per protocol for the next set of patients. If this dose was tolerated, the dose was increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients. Patients proceeded to surgical resection approximately 3-6 weeks after radiation as recommended by the ENT surgeon. Post-operatively, pathology was reviewed at the multi-disciplinary head and neck conference, and the need for adjuvant therapy was discussed. For the first 8 patients, all patients were given adjuvant therapy based on presenting features. However, after patient 8, adjuvant therapy was dictated based on high-risk pathologic features as per the NCCN guidelines and treating physician recommendations. Adjuvant radiation included intensity-modulated radiation therapy of 60 Gy in 2 Gy once-daily fraction size once-daily fraction size (total of 30 fractions). If indicated, adjuvant systemic therapy included cisplatin or other cytotoxic chemotherapy or targeted biologics (Cetuximab) per physician discretion. All patients received adjuvant durvalumab to be initiated approximately 6-12 weeks post-surgery. It was given as 1500 mg intravenously once every 4 weeks for a maximum of 6 doses, or until progression, toxicity, or withdrawal from study. This was delivered either as monotherapy or concurrently with adjuvant radiation +/- systemic therapy for high-risk patients. Safety and toxicity evaluations were done throughout the study process. DLTs and adjustment of radiation doses were done during the neoadjuvant period.

Sample Preparation:

Sampleprep ID:	SP002201
Sampleprep Summary:	Metabolomics analyses were performed as extensively described in previous studies (Issaian et al., Hematologica 2021). A volume of 20μl of frozen plasma was extracted in either 480μl of methanol:acetonitrile:water (5:3:2, v/v/v) (D'Alessandro et al. JCI Insight 2021). After vortexing at 4°C for 30 min, extracts were separated from the protein pellet by centrifugation for 10 min at 10,000g at 4°C and stored at −80°C until analysis. Ultra-High-Pressure Liquid Chromatography-Mass Spectrometry analyses were performed using a Vanquish UHPLC coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, Germany) (Nemkov et al. Methods Mol Bio 2019). Samples were analyzed using a 5-minute gradient as described ( Nemkov et al. Methods Mol Bio 2019, Nemkov et al. JCI Insight 2020). Solvents were supplemented with 0.1% formic acid for positive mode runs and 1 mM ammonium acetate for negative mode runs. MS acquisition, data analysis and elaboration were performed as described.

Sampleprep ID:

SP002201

Sampleprep Summary:

Metabolomics analyses were performed as extensively described in previous studies (Issaian et al., Hematologica 2021). A volume of 20μl of frozen plasma was extracted in either 480μl of methanol:acetonitrile:water (5:3:2, v/v/v) (D'Alessandro et al. JCI Insight 2021). After vortexing at 4°C for 30 min, extracts were separated from the protein pellet by centrifugation for 10 min at 10,000g at 4°C and stored at −80°C until analysis. Ultra-High-Pressure Liquid Chromatography-Mass Spectrometry analyses were performed using a Vanquish UHPLC coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, Germany) (Nemkov et al. Methods Mol Bio 2019). Samples were analyzed using a 5-minute gradient as described ( Nemkov et al. Methods Mol Bio 2019, Nemkov et al. JCI Insight 2020). Solvents were supplemented with 0.1% formic acid for positive mode runs and 1 mM ammonium acetate for negative mode runs. MS acquisition, data analysis and elaboration were performed as described.

Combined analysis:

Analysis ID	AN003452	AN003453
Analysis type	MS	MS
Chromatography type	Reversed phase	Reversed phase
Chromatography system	Thermo Vanquish	Thermo Vanquish
Column	Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)	Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)
MS Type	ESI	ESI
MS instrument type	Orbitrap	Orbitrap
MS instrument name	Thermo Q Exactive Orbitrap	Thermo Q Exactive Orbitrap
Ion Mode	NEGATIVE	POSITIVE
Units	Relative Abundance	Relative Abundance

Chromatography:

Chromatography ID:	CH002550
Chromatography Summary:	Negative Mode: Samples were analyzed using a 5-minute gradient as described (Nemkov et al. Methods Mol Bio 2019, Nemkov et al. JCI Insight 2020). Solvents were supplemented with 1 mM ammonium acetate for negative mode runs.
Instrument Name:	Thermo Vanquish
Column Name:	Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)
Chromatography Type:	Reversed phase

Chromatography ID:	CH002551
Chromatography Summary:	Positive Mode: Samples were analyzed using a 5-minute gradient as described (Nemkov et al. Methods Mol Bio 2019, Nemkov et al. JCI Insight 2020). Solvents were supplemented with 0.1% formic acid for positive mode runs.
Instrument Name:	Thermo Vanquish
Column Name:	Phenomenex Kinetex C18 (150 x 2.1mm,2.6um)
Chromatography Type:	Reversed phase

MS:

MS ID:	MS003215
Analysis ID:	AN003452
Instrument Name:	Thermo Q Exactive Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	MS acquisition, data analysis and elaboration were performed as described. (Nemkov et al. Methods Mol Bio 2019).
Ion Mode:	NEGATIVE

MS ID:	MS003216
Analysis ID:	AN003453
Instrument Name:	Thermo Q Exactive Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	MS acquisition, data analysis and elaboration were performed as described. (Nemkov et al. Methods Mol Bio 2019).
Ion Mode:	POSITIVE