Prediction of the Therapeutic Effects of Pembrolizumab and Nivolumab in Advanced Non-Small Cell Lung Cancer by Platelet-Derived Microparticles in Circulating Blood

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Abstract

Background:

There are limited methods to predict the therapeutic effect of immune checkpoint inhibitors (ICIs). The purpose of this study was to explore the value of circulating microparticles (MPs) in predicting thetherapeutic effects of immunotherapy.

Methods:

A prospective study was conducted at the cancer center of PLA general hospital, including all patients with advanced non-small cell lung cancer (NSCLC) who were treated with pembrolizumab or nivolumab from December 2018 to December 2019. The patients were divided into an immune-related objective response (iOR) group and an immune-related disease progression (iPD) group.The numbers of total MPs, platelet-derived microparticles (PMPs) and T-lymphocyte-derived microparticles (T-LyMPs) at baseline and after immunotherapy were detected using a flow cytometer. Univariate analysis and multivariate logistic regression analysis were used to determine the independent influencing factors.

Results:

We identified 32 patients in the iOR group and 18 patients in the iPD group. No significant difference were found intotal MPs, PMPs and T-LyMPs at the baseline between the 2 groups. While total MPs, PMPs and T-LyMPs in the iPD group were significantly higher than those in the iOR group after immunotherapy(P < 0.05). In the multivariate logistic regression analysis, PMPs ≥80 events/µL after immunotherapy(OR, 7.270; 95% CI, 1.092-48.404, P = 0.04) were associated with disease progression in advanced NSCLC and could independently predict the therapeutic effect of immunotherapy.

Conclusions:

PMPs after immunotherapy independently predicted the therapeutic effects of ICIs, making it possible to monitor the therapeutic effect in real time and rapidly adjust treatment regimens. In addition, this study found for the first time that elevated circulating T-LyMPs were associated with disease progression in advanced NSCLC.

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Most cited references 35

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New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

E A Eisenhauer, P Therasse, J. Bogaerts … (2009)

Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

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Aaron M Goodman, Shumei Kato, Lyudmila Bazhenova … (2017)

Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598-608. ©2017 AACR.

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Lesley Seymour, Jan Bogaerts, Andrea Perrone … (2017)

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden—a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline—iRECIST—was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.

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Author and article information

Journal

Journal ID (nlm-ta): Technol Cancer Res Treat

Journal ID (iso-abbrev): Technol Cancer Res Treat

Journal ID (publisher-id): TCT

Journal ID (hwp): sptct

Title: Technology in Cancer Research & Treatment

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Print): 1533-0346

ISSN (Electronic): 1533-0338

Publication date (Electronic): 22 February 2021

Publication date Collection: 2021

Volume: 20

Electronic Location Identifier: 1533033821997817

Affiliations

[1 ]Department of Respiratory and Critical Care Medicine, Second Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China

[2 ]Center of Pulmonary and Critical Care Medicine, Ringgold 104607, Chinese PLA General Hospital; , Beijing, People’s Republic of China

Author notes

[*]Hongxia Li and Xiangqun Fang, Department of Respiratory and Critical Care Medicine, Second Medical Center of Chinese PLA General Hospital, Beijing, China. Emails: lhxsls@ 123456sina.com ; fangxiangqun@ 123456hotmail.com

Author information

Tingting Liu https://orcid.org/0000-0002-1725-7748

Article

Publisher ID: 10.1177_1533033821997817

DOI: 10.1177/1533033821997817

PMC ID: 7903816

PubMed ID: 33612078

SO-VID: 79d02ef5-e861-42dd-8e2f-aa5b884d29bb

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 21 December 2020

Date revision received : 21 December 2020

Date accepted : 29 January 2021

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cover-date January-December 2021

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Keywords: platelet-derived microparticles,non-small cell lung cancer,immunotherapy,therapeutic effects

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Keywords: platelet-derived microparticles, non-small cell lung cancer, immunotherapy, therapeutic effects

Prediction of the Therapeutic Effects of Pembrolizumab and Nivolumab in Advanced Non-Small Cell Lung Cancer by Platelet-Derived Microparticles in Circulating Blood

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Cancer Immunotherapy

Most cited references 35

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics

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