scholarly journals O4 Mechanisms of lung cancer hyper-progression promoted by PD-1 immune checkpoint blockade

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A5.1-A5
Author(s):  
A Martinez-Usatorre ◽  
E Kadioglu ◽  
C Cianciaruso ◽  
B Torchia ◽  
J Faget ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Therapeutic Benefits ◽  
Angiopoietin 2

BackgroundImmune checkpoint blockade (ICB) with antibodies against PD-1 or PD-L1 may provide therapeutic benefits in patients with non-small cell lung cancer (NSCLC). However, most tumours are resistant and cases of disease hyper-progression have also been reported.Materials and MethodsGenetically engineered mouse models of KrasG12Dp53null NSCLC were treated with cisplatin along with antibodies against angiopoietin-2/VEGFA, PD-1 and CSF1R. Tumour growth was monitored by micro-computed tomography and the tumour vasculature and immune cell infiltrates were assessed by immunofluorescence staining and flow cytometry.ResultsCombined angiopoietin-2/VEGFA blockade by a bispecific antibody (A2V) modulated the vasculature and abated immunosuppressive macrophages while increasing CD8+effector T cells in the tumours, achieving disease stabilization comparable or superior to cisplatin-based chemotherapy. However, these immunological responses were unexpectedly limited by the addition of a PD-1 antibody, which paradoxically enhanced progression of a fraction of the tumours through a mechanism involving regulatory T cells and macrophages. Elimination of tumour-associated macrophages with a CSF1R-blocking antibody induced NSCLC regression in combination with PD-1 blockade and cisplatin.ConclusionsThe immune cell composition of the tumour determines the outcome of PD-1 blockade. In NSCLC, high infiltration of regulatory T cells and immunosuppressive macrophages may account for tumour hyper-progression upon ICB.Disclosure InformationA. Martinez-Usatorre: None. E. Kadioglu: None. C. Cianciaruso: None. B. Torchia: None. J. Faget: None. E. Meylan: None. M. Schmittnaegel: None. I. Keklikoglou: None. M. De Palma: None.

scholarly journals Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma

2021 ◽  
Vol 14 (9) ◽  
pp. 101170
Author(s):  
Vera Bauer ◽  
Fatima Ahmetlić ◽  
Nadine Hömberg ◽  
Albert Geishauser ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Identification of an Autophagy-Related Risk Signature Correlates With Immunophenotype and Predicts Immune Checkpoint Blockade Efficacy of Neuroblastoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenjuan Kang ◽  
Jiajian Hu ◽  
Qiang Zhao ◽  
Fengju Song
Keyword(s):  
T Cells ◽  
Risk Score ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Low Risk ◽  
Checkpoint Blockade ◽  
Gene Set Enrichment Analysis ◽  
Immune Microenvironment ◽  
Tumor Tissues

Neuroblastoma is one of the malignant solid tumors with the highest mortality in childhood. Targeted immunotherapy still cannot achieve satisfactory results due to heterogeneity and tolerance. Exploring markers related to prognosis and evaluating the immune microenvironment remain the major obstacles. Herein, we constructed an autophagy-related gene (ATG) risk model by multivariate Cox regression and least absolute shrinkage and selection operator regression, and identified four prognostic ATGs (BIRC5, GRID2, HK2, and RNASEL) in the training cohort, then verified the signature in the internal and external validation cohorts. BIRC5 and HK2 showed higher expression in MYCN amplified cell lines and tumor tissues consistently, whereas GRID2 and RNASEL showed the opposite trends. The correlation between the signature and clinicopathological parameters was further analyzed and showing consistency. A prognostic nomogram using risk score, International Neuroblastoma Staging System stage, age, and MYCN status was built subsequently, and the area under curves, net reclassification improvement, and integrated discrimination improvement showed more satisfactory prognostic predicting performance. The ATG prognostic signature itself can significantly divide patients with neuroblastoma into high- and low-risk groups; differentially expressed genes between the two groups were enriched in autophagy-related behaviors and immune cell reactions in gene set enrichment analysis (false discovery rate q -value < 0.05). Furthermore, we evaluated the relationship of the signature risk score with immune cell infiltration and the cancer-immunity cycle. The low-risk group was characterized by more abundant expression of chemokines and higher immune checkpoints (PDL1, PD1, CTLA-4, and IDO1). The risk score was significantly correlated with the proportions of CD8+ T cells, CD4+ memory resting T cells, follicular helper T cells, memory B cells, plasma cells, and M2 macrophages in tumor tissues. In conclusion, we developed and validated an autophagy-related signature that can accurately predict the prognosis, which might be meaningful to understand the immune microenvironment and guide immune checkpoint blockade.

scholarly journals Immune Checkpoint Blockade Enhances Immune Activity of Therapeutic Lung Cancer Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 655
Author(s):  
Pournima Kadam ◽  
Ram P. Singh ◽  
Michael Davoodi ◽  
Jay M. Lee ◽  
Maie St. John ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Neutralizing Antibodies ◽  
Combined Therapy ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Checkpoint Blockade ◽  
Lung Cancer Patients ◽  
Therapeutic Cancer Vaccines

Background: Immune checkpoint blockade that downregulates T cell evasion for effective immunity has provided a renewed interest in therapeutic cancer vaccines. Methods: Utilizing murine lung cancer models, we determined: tumor burden, TIL cytolysis, immunohistochemistry, flow cytometry, RNA Sequencing, CD4 T cells, CD8 T cells, CXCL9 chemokine, and CXCL10 chemokine neutralization to evaluate the efficacy of Programmed cell death protein 1 (PD-1) blockade combined with chemokine (C-C motif) ligand 21-dendritic cell tumor antigen (CCL21-DC tumor Ag) vaccine. Results: Anti-PD1 combined with CCL21-DC tumor Ag vaccine eradicated 75% of 12-day established tumors (150 mm3) that was enhanced to 90% by administering CCL21-DC tumor Ag vaccine prior to combined therapy. The effect of combined therapy was blocked by CD4, CD8, CXCL9, and CXCL10 neutralizing antibodies. Conclusion: PD-1 blockade therapy plus CCL21-DC tumor Ag vaccine could be beneficial to lung cancer patients.

scholarly journals 779 Immune checkpoint blockade impacts the suppressive phenotype and function of regulatory T cells in an endogenous mouse lymphoma model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A829-A829
Author(s):  
Vera Bauer ◽  
Fatima Ahmetlic ◽  
Martin Roecken ◽  
Ralph Mocikat ◽  
Ralph Mocikat
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Checkpoint ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Suppressive Phenotype ◽  
The Impact ◽  
Suppression Assay

BackgroundAntibodies against programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have become established part of anti-cancer therapy. However, the mechanisms contributing to the therapeutic success have not been entirely uncovered by now. Here we focus on the impact of PD-1/CTLA-4-blocking antibodies on regulatory T cells (Tregs), which are known to be involved in tumor immune evasion in many cancer types.MethodsTo evaluate how Tregs are affected by anti-PD-1/CTLA-4 therapy, we used a MYC-transgenic mouse model of spontaneously arising B-cell lymphoma, which can be effectively treated by immune checkpoint inhibition. Data were acquired by flow cytometry.ResultsAs earlier shown, Tregs were involved in immune escape of MYC tumors. The Treg to effector T cell (Teff) ratio was elevated within the CD4-positive cell compartment. Tumor-infiltrating Tregs were predominantly thymic Tregs, which recognized overexpressed tumor-derived self-peptides in an MHC class II-restricted manner and showed upregulated expression of activation markers, Foxp3, CD25 and IL-10. To examine whether these phenotypic alterations correlated with the immunosuppressive capability of Tregs, an in vitro suppression assay was established. In this setting, MYC Tregs turned out to suppress proliferation and IFN-γ release of Teff cells more effectively than wildtype Tregs. The suppression observed in vitro was mediated by cell contacts and IL-10. Further suppressive mechanisms are likely to play a role, such as competition for MHC-II ligands and a consumption of IL-2. To investigate if immune checkpoint blockade interferes with these Treg-dependent immunosuppressive pathways, MYC mice were treated with a combination of anti-PD-1 and anti-CTLA-4 antibodies. Tregs from treated MYC mice showed decreased expression of CD69, CD137, Foxp3, CD25 and IL-10 as compared to Tregs from untreated MYC mice. This correlated with a lower suppressive capacity of Tregs from treated animals in the in vitro suppression assay.ConclusionsTaken together, the data show that immune checkpoint blockade impairs the development of the suppressive phenotype of intratumoral Tregs. Thus, apart from the initially described Teff reactivation, other mechanisms are also relevant for unfolding the therapeutic effect of immune checkpoint inhibitors.Ethics ApprovalAll animal experiments were approved by Regierung von Oberbayern, approval number 55.2-1-54.

scholarly journals Clinical management of immune-related adverse events following immunotherapy treatment in patients with non-small cell lung cancer

2021 ◽  
pp. jim-2021-001806
Author(s):  
Hannah Elizabeth Green ◽  
Jorge Nieva
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Mechanism Of Action ◽  
Immune Checkpoint ◽  
Clinical Management ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Checkpoint Blockade ◽  
Small Cell Lung ◽  
Autoimmune Conditions

The advent of checkpoint blockade-based immunotherapy is rapidly changing the management of lung cancer. Whereas past anticancer drugs’ primary toxicity was hematologic, the newer agents have primarily autoimmune toxicity. Thus, it is no longer enough for oncology practitioners to be skilled only in hematology. They must also understand management of autoimmune conditions, leveraging the skills of the rheumatologist, endocrinologist and gastroenterologist in the process. Herein we describe the mechanism of action and toxicities associated with immune checkpoint blockade in patients with lung cancer and provide a framework for management of adverse events.

scholarly journals IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii108
Author(s):  
Jayeeta Ghose ◽  
Baisakhi Raychaudhuri ◽  
Kevin Liu ◽  
William Jiang ◽  
Pooja Gulati ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Survival Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Triple Combination ◽  
Triple Combination Therapy

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p < 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

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