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Plasma complement C7 as a target in non-small cell lung cancer patients to implement 3P medicine strategies

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Abstract

Background

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) significantly affect outcomes in non-small cell lung cancer (NSCLC) patients. However, differences in reactions toward PD-1/PD-L1 ICI among patients impose inefficient treatment. Therefore, developing a reliable biomarker to predict PD-1/PD-L1 ICI reaction is highly necessary for predictive, preventive, and personalized (3P) medicine.

Materials and methods

We recruited 63 patients from the National Cancer Center (NCC) and classified them into the training and validation sets. Next, 99 patients were recruited for inclusion into the external validation set at the Samsung Medical Center (SMC). Proteomic analysis enabled us to identify plasma C7 levels, which were significantly different among groups classified by their overall response to the RECIST V 1.1–based assessment. Analytical performance was evaluated to predict the PD-1/PD-L1 ICI response for each type of immunotherapy, and NSCLC histology was evaluated by determining the C7 levels via ELISA.

Results

Plasma C7 levels were significantly different between patients with and without clinical benefits (PFS ≥ 6 months). Among the groups sorted by histology and PD-1/PD-L1 immunotherapy type, only the predicted accuracy for pembrolizumab-treated patients from both NCC and SMC was greater than 73%. In patients treated with pembrolizumab, C7 levels were superior to those of the companion diagnostics 22C3 (70.3%) and SP263 (62.1%). Moreover, for pembrolizumab-treated patients for whom the PD-L1 tumor proportion score (TPS) was < 50%, the predictive accuracy of C7 was nearly 20% higher than that of 22C3 and SP263.

Conclusion

Evaluation of plasma C7 levels shows an accurate prediction of NSCLC patient reactions on pembrolizumab. It demonstrates plasma C7 is an alternative and supportive biomarker to overcome the predictive limitation of previous 22C3 and SP263. Thus, it is clear that clinical use of plasma C7 allows predictive diagnosis on lung cancer patients who have not been successfully treated with current CDx and targeted prevention on metastatic diseases in secondary care caused by a misdiagnosis of current CDx. Reduction of patients’ financial burden and increased efficacy of cancer treatment would also enable prediction, prevention, and personalization of medical service on NSCLC patients. In other words, plasma C7 provides efficient medical service and an optimized medical economy followed which finally promotes the prosperity of 3P medicine.

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Availability of data and material

All raw data and materials are available from the corresponding authors upon reasonable request.

Code availability

Not applicable

Abbreviations

3P medicine:

Predictive, preventive, and personalized medicine

C7:

Complement component 7

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death ligand 1

ICI:

Immune checkpoint inhibitor

CDx:

Companion diagnostics

NSCLC:

Non-small cell lung cancer

NCC:

National Cancer Center

SMC:

Samsung Medical Center

PFS:

Progression-free survival

OS:

Overall survival

TMB:

Tumor mutation burden

MS:

Mass spectroscopy

AGC:

Automatic gain control

HCD:

Higher-energy collisional dissociation

IACUC:

Institutional Animal Care and Use Committee

NCCI:

National Cancer Center Institute

TDLN:

Tumor-draining lymph node

ECL:

Enhanced chemiluminescence

AUC:

Area under the curve

ACC:

Accuracy

ROC:

Receiver operating characteristics

N:

Number

CR:

Complete responder

PR:

Partial responder

SD:

Stable disease

PD:

Progressive disease

responder:

Responder with clinical benefit (PFS ≥ 6 months)

Non-responder:

Non-responder without clinical benefit (PFS < 6 months)

ADC:

Adenocarcinoma

SqCC:

Squamous cell carcinoma

Other:

Other types of lung cancer

CRO:

Contract research organization

CRA:

Clinical research associate

SEN:

Sensitivity

SPE:

Specificity

PPV:

Positive predictive value

NPV:

Negative predictive value

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Funding

This study was funded by research grants from the National Cancer Center, Republic of Korea (NCC-2010161, and NCC-2110480-1), and InnoBation Bio Co., Ltd. (202000380001).

Author information

Authors and Affiliations

  1. Cancer Diagnostics Branch, Division of Clinical Research, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Gyeonggi-do, Goyang-si, 10408, Republic of Korea

    Jae Gwang Park, Eun Jung Jang, Jun Hwa Lee & Byong Chul Yoo

  2. R&D Center, InnoBation Bio Co., Ltd., 14F, K-BIZ DMC Tower, 189, Seongam-ro, Mapo-gu, Seoul, 03929, Republic of Korea

    Jae Gwang Park

  3. Biomedicine Production Branch, National Cancer Center, Goyang, Republic of Korea

    Beom Kyu Choi & Sang Myung Woo

  4. Center for Lung Cancer, National Cancer Center, Goyang, Republic of Korea

    Youngjoo Lee

  5. Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea

    Eun Jung Jang, Sang Myung Woo, Kyung-Hee Kim & Byong Chul Yoo

  6. Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea

    Sang Myung Woo

  7. Proteomics Core Facility, Research Core Center, Research Institute, National Cancer Center, Goyang, Republic of Korea

    Kyung-Hee Kim

  8. Research Center for Bioconvergence Analysis, Korea Basic Science Institute, 169-148, Gwahak-ro, Yuseong-gu, Daejeon, 34133, Republic of Korea

    Heeyoun Hwang

  9. Center for Clinical Trials, National Cancer Center, Goyang, Republic of Korea

    Wonyoung Choi

  10. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, Republic of Korea

    Se-Hoon Lee

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  1. Jae Gwang Park
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Contributions

This study was designed by JG Park, BK Choi, YJ Lee, SH Lee, and BC Yoo. Study material provision and patient recruitment were performed by YJ Lee and SH Lee. The data were collected and assembled by JG Park, BK Choi, YJ Lee, EJ Jang, SH Lee, and BC Yoo. All authors contributed to data analysis and interpretation. This manuscript was written by JG Park, BK Choi, YJ Lee, SH Lee, and BC Yoo. All authors contributed to the review and approved the final version of the manuscript. All authors had full access to all data and approved the submission of this manuscript for publication.

Corresponding authors

Correspondence to Se-Hoon Lee or Byong Chul Yoo.

Ethics declarations

Ethics approval

This study was approved by the National Cancer Center Institutional Review Board (NCC-2017-0257) and the Samsung Medical Center Institutional Review Board (SMC-2018-04-048). All animal experiments were performed in accordance with the animal experimental guidelines and were approved by the Ethics Committee of the National Cancer Center, Republic of Korea.

Consent to participate

Written informed consent was obtained for each volunteer to participate in the study.

Consent for publication

Written informed consent was obtained from each volunteer for publishing the data.

Conflict of interest

The authors declare no competing interests.

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Jae Gwang Park, Beom Kyu Choi and Youngjoo Lee are co-first authors.

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Park, J.G., Choi, B.K., Lee, Y. et al. Plasma complement C7 as a target in non-small cell lung cancer patients to implement 3P medicine strategies. EPMA Journal 12, 629–645 (2021). https://doi.org/10.1007/s13167-021-00266-x

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