The Tumour Immune Infiltrations in Immune Checkpoint Inhibitor Therapeutic Efficacy: A Computational Retrospective Study

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide. The advent of ICIs specifically targeting programmed cell death protein-1 (PD-1), or its ligand (PD-L1) represents a major therapeutic advance that is now included in standard of care regimens for non-small-cell-lung cancer (NSCLC). PD-L1 expression measured by immunohistochemistry (IHC) staining is the current gold standard predictive biomarker for immune checkpoint inhibitor (ICI) therapy in NSCLC, however many factors beyond PD-L1 expression alone affect the outcome of ICI therapy. Evaluation of other factors to better inform clinical practice will reduce both the potential for adverse immune-related toxicities and expenditure on ineffective costly therapies while potentially identifying patients otherwise missed by PD-L1 staining. The 27-gene IO assay is a RT-qPCR based gene expression panel1 that was developed to classify the tumor immune microenvironment (TIME). It has been shown to be associated with response to ICI therapy in multiple tumor types including triple negative breast cancer, metastatic urothelial carcinoma, and NSCLC where the association was independent of PD-L1 status in patients treated either with monotherapy or combination therapy.2 Currently, BC Cancer measures PD-L1 status by IHC using the PD-L1 22C3 PharmDx assay and reports the tumor proportional score (TPS) to inform clinical decision. Patients with a TPS ≥ 50% may be eligible for first-line treatment with ICI monotherapy and those with < 50% TPS are eligible for second line or later ICI monotherapy. We established this retrospective study of ICI monotherapy treated NSCLC patients to assess the 27-gene IO assay as an informative biomarker for NSCLC ICI treatment decisions.MethodsThis retrospective study is utilizing the BC Cancer Study Database to select approximately 150 patients with stage IIIB or IV NSCLC treated with single-agent ICI therapy across four BC Cancer centers from 2017 forward (figure 1). Patients are selected based on availability of adequate biopsy specimens (FFPE with at least 20% tumor content), availability of PD-L1 IHC results or sufficient tissue to conduct staining, and for whom outcome data is available via chart review. RNA from patient samples is isolated from FFPE biopsies (either primary or metastatic sites) and those that yield ≥50ng RNA will be analyzed by the 27-gene IO assay 1 to derive IO scores (IO positive or IO negative) based on previously defined thresholds.3 The association between patient outcomes on ICI monotherapy and IO scores and PD-L1 IHC will be reported and compared.Abstract 466 Figure 1Schematic representation of patient workflow forReferencesSaltman, A, et al. Prostate cancer biomarkers and multiparametric MRI: is there a role for both in prostate cancer management? Ther Adv Urol 2021;13: 1756287221997186.Ranganath HJA, Smith JR, et al. One-year progression-free survival in lung cancer patients treated with immune checkpoint inhibitors is significantly associated with a novel immunomodulatory signature but not PD-L1 staining. in SITC. Journal Immunotherapy Cancer. 2019.Nielsen, TJ, et al. A novel immuno-oncology algorithm measuring tumor microenvironment to predict response to immunotherapies. Heliyon 2021;7(3):e06438.Ethics ApprovalThe University of British Columba BC Cancer Research Ethics Board Chair, Vice-Chair or second Vice-Chair, has reviewed the above described research project, including associated documentation, and finds the research project acceptable on ethical grounds for research involving human subjects. All participants have provided informed consent before taking part in the study. REB Number H20-02635.

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Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study

Scientific Reports ◽

10.1038/s41598-020-70743-2 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Naoto Okada ◽

Rie Matsuoka ◽

Takumi Sakurada ◽

Mitsuhiro Goda ◽

Masayuki Chuma ◽

...

Keyword(s):

Risk Factors ◽

Lung Cancer ◽

Retrospective Study ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Single Institution

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Influence of Tumor Immune Infiltration on Immune Checkpoint Inhibitor Therapeutic Efficacy: A Computational Retrospective Study

Frontiers in Immunology ◽

10.3389/fimmu.2021.685370 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rong Liu ◽

Fang Yang ◽

Ji-Ye Yin ◽

Ying-Zi Liu ◽

Wei Zhang ◽

...

Keyword(s):

T Cells ◽

Immune Cells ◽

Immune Checkpoint ◽

Therapeutic Efficacy ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Progression Free Survival ◽

Cytolytic Activity ◽

Consensus Clustering ◽

Tfh Cells

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.

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Pre-Existing Diabetes Limits Survival Rate After Immune Checkpoint Inhibitor Treatment for Advanced Lung Cancer: A Retrospective Study in Japan

Diabetes Metabolic Syndrome and Obesity Targets and Therapy ◽

10.2147/dmso.s289446 ◽

2021 ◽

Vol Volume 14 ◽

pp. 773-781

Author(s):

Kaori Hisanaga ◽

Hiroshi Uchino ◽

Naoko Kakisu ◽

Masahiko Miyagi ◽

Fukumi Yoshikawa ◽

...

Keyword(s):

Lung Cancer ◽

Retrospective Study ◽

Survival Rate ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Advanced Lung Cancer ◽

Inhibitor Treatment

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Radiation pneumonitis in patients with non-small-cell lung cancer receiving chemoradiotherapy and an immune checkpoint inhibitor: a retrospective study

Radiation Oncology ◽

10.1186/s13014-021-01930-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Jeong Yun Jang ◽

Su Ssan Kim ◽

Si Yeol Song ◽

Yeon Joo Kim ◽

Sung-woo Kim ◽

...

Keyword(s):

Lung Cancer ◽

Retrospective Study ◽

Lung Volume ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Radiation Pneumonitis ◽

Checkpoint Inhibitor ◽

Significant Risk ◽

Small Cell ◽

Small Cell Lung

Abstract Background Immunotherapy has been administered to many patients with non-small-cell lung cancer (NSCLC). However, only few studies have examined toxicity in patients receiving an immune checkpoint inhibitor (ICI) after concurrent chemoradiotherapy (CCRT). Therefore, we performed a retrospective study to determine factors that predict radiation pneumonitis (RP) in these patients. Methods We evaluated the size of the planning target volume, mean lung dose (MLD), and the lung volume receiving more than a threshold radiation dose (VD) in 106 patients. The primary endpoint was RP ≥ grade 2, and toxicity was evaluated. Results After CCRT, 51/106 patients were treated with ICI. The median follow-up period was 11.5 months (range, 3.0–28.2), and RP ≥ grade 2 occurred in 47 (44.3%) patients: 27 and 20 in the ICI and non-ICI groups, respectively. Among the clinical factors, only the use of ICI was associated with RP (p = 0.043). Four dosimetric variables (MLD, V20, V30, and V40) had prognostic significance in univariate analysis for occurrence of pneumonitis (hazard ratio, p-value; MLD: 2.3, 0.009; V20: 2.9, 0.007; V30: 2.3, 0.004; V40: 2.5, 0.001). Only V20 was a significant risk factor in the non-ICI group, and MLD, V30, and V40 were significant risk factors in the ICI group. The survival and local control rates were superior in the ICI group than in the non-ICI group, but no significance was observed. Conclusions Patients receiving ICI after definitive CCRT were more likely to develop RP, which may be related to the lung volume receiving high-dose radiation. Therefore, several factors should be carefully considered for patients with NSCLC.

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