Molecular & Translational Biology of the Blood-Based VeriStrat® Proteomic Test Used in Cancer Immunotherapy Treatment Guidance
medRxiv (Cold Spring Harbor Laboratory)(2022)
摘要
INTRODUCTION The blood-based VeriStrat® proteomic test (VS) predicts patient response to therapy based on the intensities of eight different features in a mass spectrum obtained from MALDI-TOF analysis of human serum/plasma specimens. An interim analysis of the INSIGHT clinical trial ([NCT03289780][1]) demonstrated that VS labels, VS Good and VS Poor, predict patients with non-small cell lung cancer (NSCLC) who are likely sensitive or resistant to immune checkpoint inhibitor (ICI) therapy [[1][2]]. While VS measures intensities of eight spectral features by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry from patient serum/plasma samples, the individual proteoforms underlying these features have not been rigorously and comprehensively identified.
OBJECTIVES The objective of this study was to identify the proteoforms measured by VS.
METHODS Mass spectra for VS are acquired using a standard low-resolution MALDI-TOF procedure that generates broad, composite features. DeepMALDI [[2][3]] analysis of serum samples was used to resolve these features into finer peaks. Top-down proteomics analysis of human serum, combining reversed-phase fractionation and liquid chromatography – tandem mass spectrometry (LC-MS/MS), was then used to identify the key proteoform constituents of these peaks.
RESULTS It was determined that proteoforms of serum amyloid A1, serum amyloid A2, serum amyloid A4, C-reactive protein, and beta-2 microglobulin are primary constituents of the VS spectral features.
CONCLUSION Proteoforms of several proteins related to host immunity were identified as major constituents of these features. This information advances our understanding of how VS can predict patient response to therapy and opens the way for further translational studies.
Highlights
### Competing Interest Statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are current employees of and have or had stock options in Biodesix, Inc. H.R., J.R., and S.A. are inventors on patents describing DeepMALDI, assigned to Biodesix, Inc.
### Funding Statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
All samples were collected under ethics-approved protocols according to Institutional Review Board/Independent Ethics Committee requirements of the respective commercial biobanks - Discovery Life Sciences (Huntsville, AL), ProMedDx (Norton, MA), ProteoGenex (Inglewood, CA) and BioIVT (Westbury, NY) - and the PROSE study ([NCT00989690][4]). Only anonymized patient samples were used, which were not obtained through investigator intervention or interaction with the individuals. The investigators cannot readily ascertain the identity of the individual(s) to whom the coded specimens pertain because there are agreements and IRB-approved policies and procedures in place that prohibit the release of the key to the code to the investigators under any circumstances until the individuals are deceased. Therefore, this research did not involve human subjects, and neither informed consent nor IRB review were required.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Data produced in the present study are available upon reasonable request to the authors.
* B2M
: beta-2 microglobulin
CRP
: C-reactive protein
ESI
: electrospray ionization
HPLC
: high-performance liquid chromatography
ICI
: immune checkpoint inhibitor
IGF-2
: insulin-like growth factor 2
IL-6
: interleukin-6
kNN
: k-nearest neighbors
LC-MS/MS
: liquid chromatography – tandem mass spectrometry
MALDI
: matrix-assisted laser desorption/ionization
MHC I
: major histocompatibility complex class I
NSCLC
: non-small cell lung cancer
PBS
: phosphate-buffered saline
PBST
: PBS Tween
SAA
: serum amyloid A
TOF
: time-of-flight
VS
: VeriStrat
VSG
: VS Good serum pool
VSP
: VS Poor serum pool
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03289780&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F30%2F2022.12.28.22283689.atom
[2]: #ref-1
[3]: #ref-2
[4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00989690&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F30%2F2022.12.28.22283689.atom
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关键词
cancer immunotherapy,blood-based
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