P3.07-006 Pemetrexed Exerts Intratumor Immunomodulatory Effects and Enhances Efficacy of Immune Checkpoint Blockade in MC38 Syngeneic Mouse Tumor Model

Novosiadly, Ruslan D.; Schaer, David; Lu, Zhen; Amaladas, Nelusha; Luo, S.; Capen, Andrew; Meyer, Catalina M.; Manro, Jason R.; Donoho, Greg; Doman, Thompson N.; Hall, Gerald; Smeal, Tod; Kalos, Michael; Geeganage, Sandaruwan

doi:10.1016/j.jtho.2017.09.1697

Cited by 5 publications

(4 citation statements)

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“…Secondly, PDX models from EGFR mutant lung cancers were reported with poor histological differentiation, and frequent loss of EGFR mutations [34], which supported the high inconsistent risk of EGFR mutant NOG/PDX models in this study. Thirdly, the evidence that pemetrexed increased the number of TILs, and upregulated immune-related genes related to antigen presentation might support the conclusion that PDX models from patients receiving pemetrexed are less likely to maintain the original genotypes [35]. TKIs have been proved with the capability to alter the pulmonary TME, including increased CD8 + T cells and mononuclear myeloid-derived suppressor cells (M-MDSCs) (CD11b + Ly6 − G − Ly6C high ), and fewer Foxp3 + T regulatory cells (Tregs) and M2-like macrophages (CD206 + ) [36].…”

Section: Discussionmentioning

confidence: 94%

Establishment of Prediction Models for Lung Cancer NOG/PDX Models: A Guideline for Machine Learning in Small Biomedical Datasets

Guo¹,

Li²,

Qi³

et al. 2020

Preprint

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Introduction: Targeted therapy and immune checkpoint inhibitors are the most promising treatments for lung cancers but still facing multiple challenges, including resistance and individual difference. Therefore, patient-derived tumor xenografts (PDX) models are developed for drug discovery and screening. NOG mice is under the destruction of the interleukin-2 (IL-2) receptor common gamma chain, which is appropriate for building PDX models to test immunotherapies. However, current studies have little understanding of the causes of genotype mismatches in PDX or NOG/PDX models, which leads to a massive economic and time loss.Methods: Lung cancer tissues from 53 patients were obtained and engrafted into NOG mice. All of the patients' tumors and NOG/PDX models were detected for common gene mutations. Seventeen clinicopathological features were organized and input to stepwise logistic regression based on the lowest Akaike information criterion (AIC), least absolute shrinkage and selection operator (LASSO)-logistic regression, support vector machine recursive feature elimination (SVM-RFE), eXtreme Gradient Boosting (XGBoost), Gradient Boosting & Categorical Features (CatBoost), and synthetic minority over-sampling technique (SMOTE). Finally, the performance of all models was evaluated by the accuracy, area under the receiver operating characteristic curve (AUC), and F1 score in 100 testing groups.Results: Fifty-three lung cancer NOG/PDX models were successfully established, with a genotype matching rate of 79.2% (42/53). Two multivariable logistic regressions revealed that age, the number of driver mutations, epidermal growth factor receptor (EGFR) gene mutations, the type of prior chemotherapy, prior tyrosine kinase inhibitors (TKIs) therapy, and the source were potent predictors. Moreover, CatBoost (mean accuracy=0.960; mean AUC=0.939; mean F1 score=0.908) and 8-feature SVM (mean accuracy=0.950; mean AUC=0.934; mean F1 score=0.903) showed the best performance compared with the other algorithms. Moreover, the combination of SMOTE with SVM significantly improved the predictive capability (mean accuracy: 0.961 vs. 0.958, P=0.025; mean AUC: 0.940 vs. 0.935, P=0.045; mean F1 score: 0.909 vs. 0.903, P=0.047).Conclusions: We established an optimal predictive model to screen lung cancer patients for NOG/PDX models, and also offered a general approach for building prediction models in small unbalanced biomedical samples.

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Section: Discussionmentioning

confidence: 94%

Establishment of Prediction Models for Lung Cancer NOG/PDX Models: A Guideline for Machine Learning in Small Biomedical Datasets

Guo¹,

Li²,

Qi³

et al. 2020

Preprint

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“…Previous studies have suggested that chemotherapy has immunosuppressive or immune activating effects 1,2 . There have been only a few previous studies on the effects of pemetrexed on immune function, primarily on animals or in vitro studies 14,15 . It has been found that when pemetrexed is used in combination with anti‐PD‐L1 antibody, antitumor effects are increased and significant inflammation/immune activation is observed in animal experiments 3,14,16 .…”

Section: Discussionmentioning

confidence: 99%

Blood T cell diversity associated with the prognosis of advanced non‐small cell lung carcinoma treated with first‐line pemetrexed based chemotherapy

Zhang

Yaping

et al. 2021

Thoracic Cancer

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Background The tumor microenvironment is associated with prognosis in advanced non‐small cell lung carcinoma (NSCLC). The aim of this study was to explore the relationship between blood T cell diversity and survival of patients treated with pemetrexed‐based chemotherapy for nonsquamous NSCLC. Methods This prospective clinical study enrolled 26 patients with advanced NSCLC treated with 4–6 cycles of first‐line pemetrexed combined with platinum‐based therapy. The complementarity‐determining region 3 (CDR3) located in the T cell receptor beta chain (TCR β chain) was captured and deeply sequenced using next‐generation sequencing (NGS) technology, and the correlation between TCR changes and efficacy after chemotherapy was analyzed. Results Patients with an inferior quarter diversity index showed a significantly shorter progression‐free survival (PFS) than the others (median, 5.0 months vs. 8.1 months, P = 0.014). After two cycles of chemotherapy, the TCR diversity was significantly higher than the baseline (P = 0.034). Just as with the baseline, patients with an inferior quarter diversity index at the endpoint of cycle 2 showed a shorter progression‐free survival (PFS) than the others (median, 5.0 months vs. 8.4 months, P = 0.024). Conclusions In advanced NSCLC patients treated with first‐line pemetrexed combined with platinum, the low level of blood TCR diversity at baseline with an endpoint of two cycles of chemotherapy was correlated with a poor prognosis.

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“…Novosiadly et al. evaluated the preclinical profile of pemetrexed on immune response in tumor microenvironment ( 33 ). They concluded that pemetrexed enhanced T cell-mediated immunogenic cell death and increased activation and metabolic fitness of T cells.…”

Section: Discussionmentioning

confidence: 99%

Vascular Acrosyndromes Associated With Prolonged Tumor Response in Advanced Lung Cancer Patients During Treatment With Antimetabolites: A Report of Two Cases

et al. 2021

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BackgroundPemetrexed and gemcitabine are both antimetabolites drugs approved in advanced non-small cell lung cancer (NSCLC). Their toxicity profile is well known. However, rare vascular side effects can occur such as vascular acrosyndromes and especially digital ischemia. The cause of this disfiguring and painful event is still controversial. Amputation is frequently required and has been described as a predictor of poor survival outcomes.Case PresentationThis report presents two cases of vascular acrosyndrome in NSCLC patients during treatment with antimetabolites (pemetrexed and gemcitabine). Patients presented severe digital ischemia having required prostacyclin analog and chemotherapy discontinuation. In one case, symptoms improved while in the other case symptoms persisted. Both patients experienced prolonged tumor response. These findings suggest a multifactorial mechanism behind digital necrosis including an autoimmune process, which could lead to prolonged tumor control as described with immune checkpoint inhibitors.ConclusionSevere vascular acrosyndrome such as digital ischemia can occur in lung cancer patients treated with antimetabolites. Awareness needs to be raised when using these drugs in patients with predisposing factors. Whether occurrence of chemotherapy-induced immune vascular side effects might explain prolonged tumor response deserves further investigations.

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P3.07-006 Pemetrexed Exerts Intratumor Immunomodulatory Effects and Enhances Efficacy of Immune Checkpoint Blockade in MC38 Syngeneic Mouse Tumor Model

Cited by 5 publications

References 0 publications

Establishment of Prediction Models for Lung Cancer NOG/PDX Models: A Guideline for Machine Learning in Small Biomedical Datasets

Establishment of Prediction Models for Lung Cancer NOG/PDX Models: A Guideline for Machine Learning in Small Biomedical Datasets

Blood T cell diversity associated with the prognosis of advanced non‐small cell lung carcinoma treated with first‐line pemetrexed based chemotherapy

Vascular Acrosyndromes Associated With Prolonged Tumor Response in Advanced Lung Cancer Patients During Treatment With Antimetabolites: A Report of Two Cases

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