scholarly journals A Support Vector Machine Based on Liquid Immune Profiling Predicts Major Pathological Response to Chemotherapy Plus Anti-PD-1/PD-L1 as a Neoadjuvant Treatment for Patients With Resectable Non-Small Cell Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Peng ◽  
Dan Zou ◽  
Lijie Han ◽  
Zuomin Yin ◽  
Xiao Hu
Keyword(s):  
Lung Cancer ◽  
Support Vector Machine ◽  
Multivariate Analysis ◽  
Immune Cell ◽  
Small Cell ◽  
Pathological Response ◽  
Support Vector ◽  
Small Cell Lung ◽  
Radiological Response ◽  
Immune Profiling

The biomarkers for the pathological response of neoadjuvant chemotherapy plus anti-programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) (CAPD) are unclear in non-small cell lung cancer (NSCLC). Two hundred and eleven patients with stage Ib-IIIa NSCLC undergoing CAPD prior to surgical resection were enrolled, and 11 immune cell subsets in peripheral blood were prospectively analyzed using multicolor flow cytometry. Immune cell subtypes were selected by recursive feature elimination and least absolute shrinkage and selection operator methods. The support vector machine (SVM) was used to build a model. Multivariate analysis for major pathological response (MPR) was also performed. Finally, five immune cell subtypes were identified and an SVM based on liquid immune profiling (LIP-SVM) was developed. The LIP-SVM model achieved high accuracies in discovery and validation sets (AUC = 0.886, 95% CI: 0.823–0.949, P < 0.001; AUC = 0.874, 95% CI: 0.791–0.958, P < 0.001, respectively). Multivariate analysis revealed that age, radiological response, and LIP-SVM were independent factors for MPR in the two sets (each P < 0.05). The integration of LIP-SVM, clinical factors, and radiological response showed significantly high accuracies for predicting MPR in discovery and validation sets (AUC = 0.951, 95% CI: 0.916–0.986, P < 0.001; AUC = 0.943, 95% CI: 0.912–0.993, P < 0.001, respectively). Based on immune cell profiling of peripheral blood, our study developed a predictive model for the MPR of patients with NSCLC undergoing CAPD treatment that can potentially guide clinical therapy.

scholarly journals Weighted-Support Vector Machine Learning Classifier of Circulating Cytokine Biomarkers to Predict Radiation-Induced Lung Fibrosis in Non-Small-Cell Lung Cancer Patients

2021 ◽  
Vol 10 ◽  
Author(s):  
Hao Yu ◽  
Ka-On Lam ◽  
Huanmei Wu ◽  
Michael Green ◽  
Weili Wang ◽  
...  
Keyword(s):  
Machine Learning ◽  
Lung Cancer ◽  
Support Vector Machine ◽  
Small Cell Lung Cancer ◽  
Lung Fibrosis ◽  
Small Cell ◽  
Support Vector ◽  
Svm Classifier ◽  
Small Cell Lung ◽  
Radiation Induced

BackgroundRadiation-induced lung fibrosis (RILF) is an important late toxicity in patients with non-small-cell lung cancer (NSCLC) after radiotherapy (RT). Clinically significant RILF can impact quality of life and/or cause non-cancer related death. This study aimed to determine whether pre-treatment plasma cytokine levels have a significant effect on the risk of RILF and investigate the abilities of machine learning algorithms for risk prediction.MethodsThis is a secondary analysis of prospective studies from two academic cancer centers. The primary endpoint was grade≥2 (RILF2), classified according to a system consistent with the consensus recommendation of an expert panel of the AAPM task for normal tissue toxicity. Eligible patients must have at least 6 months’ follow-up after radiotherapy commencement. Baseline levels of 30 cytokines, dosimetric, and clinical characteristics were analyzed. Support vector machine (SVM) algorithm was applied for model development. Data from one center was used for model training and development; and data of another center was applied as an independent external validation.ResultsThere were 57 and 37 eligible patients in training and validation datasets, with 14 and 16.2% RILF2, respectively. Of the 30 plasma cytokines evaluated, SVM identified baseline circulating CCL4 as the most significant cytokine associated with RILF2 risk in both datasets (P = 0.003 and 0.07, for training and test sets, respectively). An SVM classifier predictive of RILF2 was generated in Cohort 1 with CCL4, mean lung dose (MLD) and chemotherapy as key model features. This classifier was validated in Cohort 2 with accuracy of 0.757 and area under the curve (AUC) of 0.855.ConclusionsUsing machine learning, this study constructed and validated a weighted-SVM classifier incorporating circulating CCL4 levels with significant dosimetric and clinical parameters which predicts RILF2 risk with a reasonable accuracy. Further study with larger sample size is needed to validate the role of CCL4, and this SVM classifier in RILF2.

scholarly journals Meta-Analysis of Neoadjuvant Immunotherapy for Patients with Resectable Non-Small Cell Lung Cancer

2021 ◽  
Vol 28 (6) ◽  
pp. 4686-4701
Author(s):  
Christopher Cao ◽  
Anthony Le ◽  
Matthew Bott ◽  
Jeffrey Yang ◽  
Dominique Gossot ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Meta Analysis ◽  
Small Cell ◽  
Pathological Response ◽  
Small Cell Lung ◽  
Complete Pathological Response ◽  
Neoadjuvant Immunotherapy ◽  
Radiological Response

Purpose: Immunotherapy has created a paradigm shift in the treatment of metastatic non-small cell lung cancer (NSCLC), overcoming the therapeutic plateau previously achieved by systemic chemotherapy. There is growing interest in the utility of immunotherapy for patients with resectable NSCLC in the neoadjuvant setting. The present systematic review and meta-analysis aim to provide an overview of the existing evidence, with a focus on pathological and radiological response, perioperative clinical outcomes, and long-term survival. Methods: A systematic review was conducted using electronic databases from their dates of inception to August 2021. Pooled data on pathological response, radiological response, and perioperative outcomes were meta-analyzed where possible. Results: Eighteen publications from sixteen studies were identified, involving 548 enrolled patients who underwent neoadjuvant immunotherapy, of whom 507 underwent surgery. Pathologically, 52% achieved a major pathological response, 24% a complete pathological response, and 20% reported a complete pathological response of both the primary lesion as well as the sampled lymph nodes. Radiologically, 84% of patients had stable disease or partial response. Mortality within 30 days was 0.6%, and morbidities were reported according to grade and frequency. Conclusion: The present meta-analysis demonstrated that neoadjuvant immunotherapy was feasible and safe based on perioperative clinical data and completion rates of surgery within their intended timeframe. The pathological response after neoadjuvant immunotherapy was superior to historical data for patients who were treated with neoadjuvant chemotherapy alone, whilst surgical and treatment-related adverse events were comparable. The limitations of the study included the heterogenous treatment regimens, lack of long-term follow-up, variations in the reporting of potential prognostic factors, and potential publication bias.

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

scholarly journals Preoperative nivolumab to evaluate pathological response in patients with stage I non-small cell lung cancer: a study protocol of phase II trial (POTENTIAL)

BMJ Open ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. e043234
Author(s):  
Atsushi Kagimoto ◽  
Yasuhiro Tsutani ◽  
Takahiro Mimae ◽  
Yoshihiro Miyata ◽  
Norihiko Ikeda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
High Risk ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Phase Ii Trial ◽  
Clinical Stage ◽  
Small Cell ◽  
Pathological Response ◽  
Stage I ◽  
Small Cell Lung

IntroductionRecently, inhibition of programmed cell death 1 or its ligand has shown therapeutic effects on non-small cell lung cancer (NSCLC). However, the effectiveness of preoperative nivolumab monotherapy for stage I NSCLC remains unknown. The present study aimed to investigate the pathological response of preoperative treatment with nivolumab for clinically node negative but having a high risk of NSCLC recurrence.Methods and analysisThe Preoperative Nivolumab (Opdivo) to evaluate pathologic response in patients with stage I non-small cell lung cancer: a phase 2 trial (POTENTIAL) study is a multicentre phase II trial investigating efficacy of preoperative nivolumab for clinical stage I patients at high risk of recurrence. This study includes histologically or cytologically confirmed NSCLC patients with clinical N0 who were found on preoperative high-resolution CT to have a pure solid tumour without a ground-glass opacity component (clinical T1b, T1c or T2a) or a solid component measuring 2–4 cm in size (clinical T1c or T2a). Patients with epidermal growth factor receptor (EGFR) mutation (deletion of exon 19 or point mutation on exon21, L858R), anaplastic lymphoma kinase (ALK) translocation or c-ros oncogene 1 (ROS-1) translocation are excluded from this study. Nivolumab (240 mg/body) is administrated intravenously as preoperative therapy every 2 weeks for three cycles. Afterward, lobectomy and mediastinal lymph node dissection (ND 2a-1 or ND 2a-2) are performed. The primary endpoint is a pathological complete response in the resected specimens. The secondary endpoints are safety, response rates and major pathological response. The planed sample size is 50 patients. Patients have been enrolled since April 2019.Ethics and disseminationThis trial was approved by the Institutional Review Board of Hiroshima University Hospital and other participating institutions. This trial will help examine the efficacy of preoperative nivolumab therapy for clinical stage I NSCLC.Trial registration numberjRCT2061180016.

scholarly journals P1.04-03 Suppressive Immune Cell Profiling in Patients with Non-Small Cell Lung Cancer

2018 ◽  
Vol 13 (10) ◽  
pp. S526
Author(s):  
J. Koh ◽  
K.Y. Lee ◽  
B. Kim ◽  
M.S. Kim ◽  
H.J. Cho ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design

2021 ◽  
Vol 17 (12) ◽  
pp. 1459-1472
Author(s):  
Pilar Garrido ◽  
Jean-Louis Pujol ◽  
Edward S Kim ◽  
Jay M Lee ◽  
Masahiro Tsuboi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Neoadjuvant Treatment ◽  
Small Cell ◽  
Pathological Response ◽  
Small Cell Lung ◽  
Clinical Trial Registration ◽  
Lung Cancer Patients ◽  
Randomized Phase Ii

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. Clinical trial registration: NCT03968419 (ClinicalTrials.gov)

scholarly journals 962 Integrative immunomics highlight the immunomodulatory impact of neoadjuvant chemotherapy and immune-based treatments in resected non-small-cell lung cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A1013-A1013
Author(s):  
Stephanie Schmidt ◽  
Younghee Lee ◽  
Cheuk Leung ◽  
Lorenzo Federico ◽  
Heather Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Immune Activation ◽  
Therapeutic Efficacy ◽  
Small Cell ◽  
Effector T Cells ◽  
Small Cell Lung ◽  
Immune Profiling

BackgroundHow neoadjuvant chemo-immunotherapy modulates tumor immune composition and response is not completely understood. We interrogate immunomodulation of neoadjuvant platinum-based chemotherapy (C), nivolumab (N), and N-plus-C (NC) and their connections to therapeutic efficacy in resected non-small cell lung cancer (NSCLC) by integrating immunomic data from the ImmunogenomiC PrOfiling of NSCLC (ICON) study and NEOSTAR trial cohorts.MethodsIn NEOSTAR (NCT03158129), patients with stage I-IIIA (single N2) resectable NSCLC (AJCC7th) received N (3 mg/kg IV, D1,15,29); patients with stage IB(≥4cm)-IIIA (single N2) resectable NSCLC received NC (N 360 mg IV plus C, D1,22,43 for 3 cycles, every 3 weeks) before surgery; major pathologic response (MPR) was the primary endpoint. In ICON, patients with stage IB(≥4cm)-IIIA resectable NSCLC received C before surgery. Surgically resected tumor samples underwent immune profiling via flow cytometry (n=16,13,9 for C,N,NC), immunohistochemistry (IHC;n=0,18,14), and multiplexed immunofluorescence (mIF;n=28,16,10). Treatment-associated immunomodulation and associations with therapeutic efficacy were analyzed using: 1) a shared nearest neighbors-based network we developed linking measurements across datasets; 2) MetaCyto, a specialized cytometry analysis method for identifying cell subsets by clustering.ResultsWe holistically explored the immunomic data by integration across cohorts. Through hierarchical regression of the integrated data, we determined the overall effect of a given treatment controlling for the presence or absence of the other treatment.We examined C’s effects across all cohorts controlling for N. Across all patients, regardless of MPR, C is associated with immunosuppression, increasing PD1+ T cell (CD45+CD3+) populations: regulatory (CD4+CD25+FOXP3+), helper (CD4+), and effector (CD8+) (effect size(ES):1.48,1.61,1.26;q<0.05). C also decreases proliferative (Ki67+) populations: helper and effector T cells as well as NK (CD45+CD3-CD56+) cells (ES:-1.27,-1.43;-1.36;q<0.05). In patients without MPR (i.e., non-responding patients), immunosuppression appears heightened by increased Ki67+ regulatory T cells (ES:1.86;q<0.05).Conversely, we examined N’s effects across all cohorts controlling for C. Across all patients, regardless of MPR, N is associated with immune activation, increasing ICOS+ T cell populations: regulatory, helper, and effector (ES:1.29,1.29,1.47;q<0.05). Comparing N and NC reveals that adding C may drive exhaustion by increasing TIM3+ regulatory, helper and effector T cells (ES:1.16,1.17,1.23;q<0.05), an effect more pronounced in non-responding patients (ES:1.31,1.33,1.35;q<0.05).ConclusionsWe report the first integrated examination of the immunomodulatory effect of neoadjuvant C and N. C is associated with immunosuppression while N with immune activation; together, N appears to lessen C’s suppressive effects. Incorporation of transcriptomics into this integrated network of flow cytometry, mIF, and IHC immune profiling data is ongoing to augment translational insights for neoadjuvant chemo/immunotherapies.

scholarly journals Survival Outcomes of Local Compared With Systemic First Treatment of Non-Small Cell Lung Cancer Brain Metastases

2021 ◽  
Vol 11 ◽  
Author(s):  
Hong-Mei Liu ◽  
Chun-Liu Meng ◽  
Lu-Jun Zhao
Keyword(s):  
Lung Cancer ◽  
Multivariate Analysis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Stereotactic Radiosurgery ◽  
Systemic Treatment ◽  
Clinical Symptoms ◽  
Local Treatment ◽  
Small Cell ◽  
Small Cell Lung

ObjectiveThis retrospective study evaluated the survival advantage of local treatment targeted to brain metastases, relative to systemic therapy, as the first option for brain metastases of non-small cell lung cancer (NSCLC).MethodsFirst reviewed were 291 cases of NSCLC brain metastases from two centers. All patients were at least 18 years old, with histologically confirmed NSCLC, and required and underwent both local (radiotherapy or brain surgery) and systemic treatment (chemotherapy and tyrosine kinase inhibitor [TKI] medication). Demographics, clinical characteristics, and treatment-related variables were collected.ResultsThe final population comprised 160 patients. Overall, the multivariate analysis suggested that the following were associated with better survival: &gt;3 cycles of chemotherapy; stereotactic radiosurgery; and TKI medication (all, P = 0.000). Local treatment that began within 1 week of the diagnosis of brain metastases was associated with poorer survival (P = 0.006). Among the 111 patients with symptomatic brain metastases, the multivariate analysis indicated that better survival was associated with &gt;3 cycles of chemotherapy (P = 0.000), radiation dose &gt;40 Gy (P = 0.001), stereotactic radiosurgery (P = 0.000), and TKI medication (P = 0.000), while local treatment that began within 1 week after the diagnosis of brain metastases was associated with poorer survival (P = 0.015).ConclusionsFor patients with NSCLC brain metastases, regardless of the presence of clinical symptoms associated with brain metastases, systemic treatment before local may be better for survival. Even when used to relieve clinical symptoms, local treatment should be within a setting of sufficient systemic treatment.

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