scholarly journals Phase II study of pembrolizumab in refractory esophageal cancer with correlates of response and survival

2021 ◽  
Vol 9 (9) ◽  
pp. e002472
Author(s):  
Leonie K de Klerk ◽  
Anuj K Patel ◽  
Sarah Derks ◽  
Eirini Pectasides ◽  
Jeremy Augustin ◽  
...  
Keyword(s):  
Cell Death ◽  
Esophageal Cancer ◽  
Programmed Cell Death ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Interleukin 2 ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Peripheral Blood Mononuclear

BackgroundImmune checkpoint inhibitors have revolutionized cancer treatment, but the benefits in refractory patients with esophageal cancer have been modest. Predictors of response as well as new targets for novel therapeutic combinations are needed. In this phase 2 clinical trial, we tested single-agent pembrolizumab in patients with advanced esophageal cancer, who received at least one prior line of therapy.MethodsPembrolizumab 200 mg every 3 weeks was tested in 49 patients with refractory esophageal cancer: 39 with adenocarcinoma and 10 with esophageal squamous cell carcinoma. Major endpoints were radiological response by Immune-related Response Evaluation Criteria In Solid Tumors and survival. Tumor samples were evaluated for programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and immune contexture by both NanoString mRNA expression analysis and flow cytometry. Peripheral blood mononuclear cells and a panel of circulating chemokines were also analyzed.ResultsThe overall response rate (ORR) was 8% (4 of 49 patients; 95% CI 2.3% to 19.6%). Median overall survival (OS) was 5.8 months (95% CI 4.0 to 9.5). ORR and OS were not associated with histology. For PD-L1-positive patients, ORR was 13.3% (95% CI 1.7% to 40.5%) and median OS was 7.9 months (95% CI 4.7 to 15.5). A trend toward improved OS was observed in seven patients with a TMB ≥10 mut/Mb (p=0.086). Tumors with a PD-L1 Combined Positive Score ≥1 showed enrichment of LAG3 (p=0.005) and IDO1 (p=0.04) gene expression. Baseline levels of circulating CXCL10, interleukin 2 (IL2) receptor α (IL2RA) and IL6 were associated with survival: CXCL10 favorably, (HR 0.37, p=0.002 (progression-free survival); HR 0.55, p=0.018 (OS)); IL2RA and IL6 unfavorably (HR 1.57, p=0.020 for IL6 (OS); HR 2.36, p=0.025 for IL2RA (OS)).ConclusionsPembrolizumab monotherapy was modestly effective in refractory esophageal cancer. Circulating CXCL10 at baseline appeared to be a robust predictor of response. Other T cell exhaustion markers are upregulated in PD-L1-positive patients, suggesting that immunotherapy combinations such as anti-LAG3/programmed cell death protein 1 (PD-1) or anti-IDO1/PD-1 may be of promise in refractory esophageal cancer.

scholarly journals Design and Synthesis of Novel Peptidomimetics for Cancer Immunotherapy

2020 ◽  
Author(s):  
Ceyda Köse ◽  
Esra Uysal ◽  
Büşra Yazıcı ◽  
Zeynep Tuğay ◽  
Serap İpek Dingiş Birgül ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Peripheral Blood Mononuclear ◽  
Design And Synthesis ◽  
Viability Assay ◽  
Immune Mediated

Tumor cells benefit from some certain signals, which are referred to as “immune checkpoints”, to escape immune-mediated destruction. With that in mind, it is believed that the blockade of these points, such as programmed cell death Ligand-1 (PD-L1) and programmed cell death 1 (PD-1), can restore an adaptative immune response against tumoral cells. In this study, we have designed and synthesized some novel peptidomimetics with a 2-aminobenzathiazole scaffold, which targets the PD-1/PDL-1 pathway. In the viability assay, it was found that these compounds decreased the proliferation of peripheral blood mononuclear cells in the concentration of 10 uM. Overall, our results indicate that these novel compounds are potential checkpoint inhibitors for cancer immunotherapy.

scholarly journals Design and Synthesis of Novel Peptidomimetics for Cancer Immunotherapy

2020 ◽  
Author(s):  
Ceyda Köse ◽  
Esra Uysal ◽  
Büşra Yazıcı ◽  
Zeynep Tuğay ◽  
Serap İpek Dingiş Birgül ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Peripheral Blood Mononuclear ◽  
Design And Synthesis ◽  
Viability Assay ◽  
Immune Mediated

Tumor cells benefit from some certain signals, which are referred to as “immune checkpoints”, to escape immune-mediated destruction. With that in mind, it is believed that the blockade of these points, such as programmed cell death Ligand-1 (PD-L1) and programmed cell death 1 (PD-1), can restore an adaptative immune response against tumoral cells. In this study, we have designed and synthesized some novel peptidomimetics with a 2-aminobenzathiazole scaffold, which targets the PD-1/PDL-1 pathway. In the viability assay, it was found that these compounds decreased the proliferation of peripheral blood mononuclear cells in the concentration of 10 uM. Overall, our results indicate that these novel compounds are potential checkpoint inhibitors for cancer immunotherapy.

scholarly journals Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist

2021 ◽  
Vol 9 (1) ◽  
pp. e001762
Author(s):  
Punit Upadhyaya ◽  
Johanna Lahdenranta ◽  
Kristen Hurov ◽  
Sailaja Battula ◽  
Rachel Dods ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cancer Therapeutics ◽  
Peripheral Blood Mononuclear ◽  
Tnf Superfamily

BackgroundIn contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides (Bicycles).MethodsPhage libraries displaying Bicycles were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1. The CD137 and OX40 Bicycles were chemically conjugated to tumor antigen Bicycles with different linkers and stoichiometric ratios of binders to obtain a library of low molecular weight TICAs (MW <8 kDa). The TICAs were evaluated in a suite of in vitro and in vivo assays to characterize their pharmacology and mechanism of action.ResultsLinking Bicycles against costimulatory receptors (e.g., CD137) to Bicycles against tumor antigens (e.g., EphA2) created potent agonists that activated the receptors selectively in the presence of tumor cells expressing these antigens. An EphA2/CD137 TICA (BCY12491) efficiently costimulated human peripheral blood mononuclear cells in vitro in the presence of EphA2 expressing tumor cell lines as measured by the increased secretion of interferon γ and interleukin-2. Treatment of C57/Bl6 mice transgenic for the human CD137 extracellular domain (huCD137) bearing EphA2-expressing MC38 tumors with BCY12491 resulted in the infiltration of CD8+ T cells, elimination of tumors and generation of immunological memory. BCY12491 was cleared quickly from the circulation (plasma t1/2 in mice of 1–2 hr), yet intermittent dosing proved effective.ConclusionTumor target-dependent CD137 agonism using a novel chemical approach (TICAs) afforded elimination of tumors with only intermittent dosing suggesting potential for a wide therapeutic index in humans. This work unlocks a new path to effective cancer immunotherapy via agonism of TNF superfamily receptors.

Association of reinvigoration of circulating anti-telomerase CD4 Th1 response in cancer patients with anti-PD-1 response.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3044-3044 ◽  
Author(s):  
Emeline Orillard ◽  
Laura Boullerot ◽  
Caroline Laheurte ◽  
Amandine Martin ◽  
Marion Jacquin ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Advanced Cancer Patients ◽  
Peripheral Blood Mononuclear ◽  
Th1 Response

3044 Background: Increasing evidence highlights the crucial roles played by CD4+ Th1 cells in cancer immunity and immunotherapy (Spitzer et al., Cell 2017, Borst et al., Nat rev Immunol 2018). Here, we investigate the relevance of circulating CD4 Th1 response against shared tumor-associated antigens (TAA) in cancer patients treated by anti-PD-1 immunotherapy. Methods: A total of 46 advanced cancer patients (pts) including 32 pts with non-small cell lung cancer (NSCLC), 14 pts with melanoma, were enrolled (ITHER trial NCT02840058). Patients were treated with anti-PD-1 therapy as standard of care (26 pts with nivolumab and 20 pts with pembrolizumab). Peripheral blood mononuclear cells were collected before and after treatment at 1 and 3 months. The presence of circulating TAA-specific Th1 response was measured by IFNy ELISPOT assay using a mixture of 15mer peptides derived from telomerase (TERT) (Laheurte et al., Oncoimmunology 2016 and Br J C 2019). Results: At the baseline, the anti-TERT Th1 response was observed in 37% of pts. After anti-PD-1 therapy, de novo induction and/or amplification of pre-existing anti-TERT Th1 response was found in 26 % of pts (12/46). Whereas, a decrease of this response was documented in 15% of pts (7/46).The presence of anti-TERT Th1 response in peripheral blood during anti-PD-1 treatment was associated with a prolonged progression free-survival (PFS) as compared to the immune non responder pts (14.4 vs 2.6 months respectively, p = 0.006, HR 0.39 [0.2;0.76]). Similar observation was made for the overall survival (OS) (22.3 vs 12.3 months respectively, p = 0.04 HR 0.45 [0.21;0.96]). Notably, de novo reinvigoration of peripheral anti-TERT Th1 response after anti-PD-1 therapy was associated with a better clinical outcome as compared to the group of pts with decreased immune response after treatment (Median OS not reached vs 5.8 months). In contrast, no association with anti-PD-1 response was observed neither with circulating anti-NY-ESO-1 or with anti-viral Th1 response, concurrently measured in these patients. Conclusions: The reinvigoration of circulating CD4 Th1 against telomerase in patients treated by anti-PD-1 is associated with a better clinical outcome. These results underline the potential interest of monitoring circulating antitumor CD4 Th1 response for immune checkpoint inhibitors management.

Rapid expansion of M-MDSCs and association with high levels of plasma TSLP and primary resistance to PD-1 inhibitors in metastatic NSCLC.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3084-3084
Author(s):  
Sally CM Lau ◽  
Stephanie WY Wong ◽  
Ben X Wang ◽  
Devalben Patel ◽  
Aline Fusco Fares ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Suppressor Cell ◽  
Poor Response ◽  
Rapid Expansion ◽  
Blood Collection ◽  
Primary Resistance ◽  
Peripheral Blood Mononuclear

3084 Background: Elevated frequency of peripheral myeloid cell populations has consistently been associated with poor response to immune checkpoint inhibitors (ICI) in metastatic non-small cell lung cancer (mNSCLC). The mechanisms underlying this relationship remains poorly understood. Thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation, has been implicated in a complex feedback loop leading to tumor growth and expansion of myeloid populations. We hypothesized that TSLP levels directly correlate with the presence and expansion of myeloid derived suppressor cell (MDSC) populations and sought to explore their association with response to PD-1 inhibitors in mNSCLC. Methods: mNSCLC patients treated with ICIs underwent baseline and serial blood collection. Peripheral blood mononuclear cells (PBMC) were analyzed by high-dimensional flow cytometry using validated panels to evaluate T/B/NK-cell, Treg and myeloid populations. Plasma cytokines including TSLP were analyzed using ELISA and Luminex assays. Cox and logistic regressions were utilized to correlate biomarkers with progression-free survival (PFS), overall survival (OS) and radiographic response. Results: 30 mNSCLC patients treated with single-agent ICI were included in the analysis. TSLP level was significantly associated with expansion of monocytic(M)-MDSCs in response to ICI treatment (p=0.02). M-MDSC frequency after a median of 20 days of ICI treatment was significantly associated with progressive disease (PD), reduced PFS and OS (all p<0.05) whereas no correlation was seen with baseline M-MDSC frequency. Patients with a doubling of M-MDSCs (n=11) after treatment had a primary PD rate of 64% vs 24% (OR 7.0, p=0.04) and significantly worse median PFS (2.5 vs 7.8 months, HR 2.6 p=0.04). Conclusions: Early expansion of circulating M-MDSCs after treatment with PD-1 inhibitors is associated with elevated baseline TSLP levels and primary disease progression following ICI therapy in mNSCLC. These findings suggest that elevated TSLP and early expansion of myeloid populations may represent an important mechanism of primary resistance to PD-1 inhibitors in mNSCLC.

scholarly journals Lack of Efficacy of Bevacizumab Plus Irinotecan in Children With Recurrent Malignant Glioma and Diffuse Brainstem Glioma: A Pediatric Brain Tumor Consortium Study

2010 ◽  
Vol 28 (18) ◽  
pp. 3069-3075 ◽  
Author(s):  
Sridharan Gururangan ◽  
Susan N. Chi ◽  
Tina Young Poussaint ◽  
Arzu Onar-Thomas ◽  
Richard J. Gilbertson ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Pediatric Brain Tumor ◽  
Progression Free Survival ◽  
Brainstem Glioma ◽  
Recurrent Malignant Glioma ◽  
Peripheral Blood Mononuclear

Purpose A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG). Patients and Methods Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast–enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ. Results Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure. Conclusion BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.

scholarly journals Peripheral Blood Mononuclear Cells Induce Programmed Cell Death in Human Endothelial Cells and May Prevent Repair: Role of Cytokines

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 1931-1938 ◽  
Author(s):  
Heidrun Lindner ◽  
Ernst Holler ◽  
Birgit Ertl ◽  
Gabriele Multhoff ◽  
Manuela Schreglmann ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Blood Mononuclear Cells

Abstract Human umbilical vein endothelial cells (HUVECs) undergo programmed cell death (apoptosis) after coculture with peripheral blood mononuclear cells (PBMCs) preactivated by ionizing radiation (IR) or by bacterial endotoxin (lipopolysaccharide [LPS]). Cell-to-cell contact-mediated apoptosis could be blocked in both cases by anti–tumor necrosis factor-α (anti–TNF-α) monoclonal antibody MAK195 and also by the antagonistic cytokine interleukin-10 (IL-10). Cell-free PBMC supernatants from both preactivation treatments were sufficient to trigger endothelial apoptosis. In contrast, MAK195 and IL-10 were found to be ineffective in this system, suggesting a TNF-α–independent mechanism. However, N-Acetylcystein, an antioxidant, fully abrogated programmed cell death mediated by the supernatant of IR-treated PBMCs, but not of LPS-treated PBMCs. Additionally, we found that coculture and cell-free supernatants of preactivated as well as untreated PBMCs caused cell cycle arrest in proliferating EC in G0/1 , which could be relieved by IL-10, but not by anti–TNF-α. Further analysis showed that transforming growth factor-β, which was constitutively expressed in the supernatant of PBMCs, namely lymphocytes, was responsible for this. These data suggest a pathophysiologic model in which preactivated PBMCs cause EC damage and may prevent blood vessel repair by arresting the proliferation of ECs. This could contribute to the understanding of various clinical endothelial complications that occur after irradiation as well as in cases of endotoxemia or related inflammatory states.

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