Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression

2017 ◽  
Vol 16 (4) ◽  
pp. 671-680 ◽  
Author(s):  
Andrew J. Garton ◽  
Scott Seibel ◽  
Lori Lopresti-Morrow ◽  
Linda Crew ◽  
Neal Janson ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Antibody Treatment ◽  
Monoclonal Antibody Treatment

scholarly journals Opportunities for using in silico‐based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors

2020 ◽  
Vol 86 (9) ◽  
pp. 1769-1777 ◽  
Author(s):  
Cody J. Peer ◽  
Daniel A. Goldstein ◽  
Jennifer C. Goodell ◽  
Ryan Nguyen ◽  
William D. Figg ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Checkpoint ◽  
In Silico ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Dosing Regimens

scholarly journals Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Jianxing Tang ◽  
Qian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Tumor Models ◽  
Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

The antitumor activity of alternating electric fields (TTFields) in combination with immune checkpoint inhibitors.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e14570-e14570 ◽  
Author(s):  
Moshe Giladi ◽  
Tali Voloshin ◽  
Anna Shteingauz ◽  
Mijal Munster ◽  
Roni Blat ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Electric Fields ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Alternating Electric Fields

Evaluation of the clinical benefits of immune checkpoint inhibitors in patients with advanced melanoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 194-194
Author(s):  
Qiyun Ou ◽  
Yunfang Yu ◽  
Dagui Lin ◽  
Tuping Fu ◽  
Quanlong Gao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Advanced Melanoma ◽  
Combination Immunotherapy ◽  
Wild Type ◽  
Clinical Benefits

194 Background: Immune checkpoint inhibitors selection in advanced melanoma is complicated further, with choices among anti-CTLA4 or anti-PD-1 therapeutic antibodies options. We aimed to evaluate the clinical benefits of immune checkpoint inhibitors for discussing evidence-based treatment strategies by a meta-analysis of randomized clinical trials (RCTs) data. Methods: We searched for RCTs investigating immune checkpoint inhibitors in patients with advanced melanoma until September 2017. Hazard ratios (HRs) was estimated for overall survival (OS) and progression-free survival (PFS). The quality of the evidence was evaluated with the GRADE framework. Results: Overall, 18 RCTs including a total of 8,917 patients were identified. Immune checkpoint inhibitors versus placebo or observation prolonged PFS (HR = 0.59, 95% confidence interval (CI) 0.44 to 0.78, P < 0.0001) and OS (HR = 0.77, 95% CI 0.72 to 0.84, P < 0.0001). The combination immunotherapy had significantly higher benefit than monotherapy for PFS (HR = 0.75, 95% CI 0.61 to 0.92, P = 0.005) and OS (HR = 0.70, 95% CI 0.61 to 0.79, P < 0.0001). Treatment with anti-PD-1 monoclonal antibody was associated with improved PFS (HR = 0.61, 95% CI 0.59 to 0.69, P < 0.0001) and OS (HR = 0.66, 95% CI 0.58 to 0.77, P < 0.0001) compared with anti-CTLA-4 monoclonal antibody. According to BRAF status analysis, there was a PFS benefit of immune checkpoint inhibitors versus placebo or observation (mutant, HR = 0.58, 95% CI 0.35 to 0.96, P = 0.035; wild–type, HR = 0.52, 95% CI 0.43 to 0.69, P = 0.001), anti-PD-1 outperformed anti-CTLA-4 checkpoint inhibitor (mutant, PFS HR = 0.64, 95% CI 0.51 to 0.79, P < 0.0001; wild–type, PFS HR = 0.58, 95% CI 0.47 to 0.71, P < 0.0001); and combination compared with single-agent immunotherapy (mutant, HR = 0.38, 95% CI 0.15 to 0.98, P = 0.046; wild–type, HR = 0.40, 95% CI 0.23 to 0.69, P = 0.001). Conclusions: This analysis provides an evidence that immune checkpoint inhibitors enhanced OS and PFS in patients with advanced melanoma, as well as combination immunotherapy and anti-PD-1 monoclonal antibody appear to be clinically beneficial option preference.

scholarly journals Silencing of VEGFR2 by RGD-Modified Lipid Nanoparticles Enhanced the Efficacy of Anti-PD-1 Antibody by Accelerating Vascular Normalization and Infiltration of T Cells in Tumors

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3630
Author(s):  
Riki Cho ◽  
Yu Sakurai ◽  
Haleigh Sakura Jones ◽  
Hidetaka Akita ◽  
Akihiro Hisaka ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Lipid Nanoparticles ◽  
Vascular Normalization ◽  
Tumor Endothelial Cells

Despite the promising anticancer effects of immune checkpoint inhibitors, their low objective response rate remains to be resolved; thus, combination therapies have been investigated. We investigated the combination of an anti-programmed cell death 1 (aPD-1) monoclonal antibody with the knockdown of vascular endothelial factor receptor 2 (VEGFR2) on tumor endothelial cells to overcome resistance to immune checkpoint inhibitors and improve the objective response rate. The successful delivery of small interfering RNA to tumor endothelial cells was achieved by RGD peptide-modified lipid nanoparticles composed of a novel, pH-sensitive, and biodegradable ssPalmO-Phe. RGD-modified lipid nanoparticles efficiently induced the knockdown of VEGFR2 in tumor endothelial cells (TECs), which induced vascular normalization. The combination of a PD-1 monoclonal antibody with Vegfr2 knockdown enhanced CD8+ T cell infiltration into tumors and successfully suppressed tumor growth and improved response rate compared with monotherapy. Our combination approach provides a promising strategy to improve therapeutic outcomes in immune checkpoint inhibitor-resistant cancers.

scholarly journals Antiangiogenic Antibody BD0801 Combined With Immune Checkpoint Inhibitors Achieves Synergistic Antitumor Activity and Affects the Tumor Microenvironment

2021 ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Qian Wang ◽  
Feng Li ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Antiangiogenic Agents ◽  
Anti Vegf

Abstract Background: signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on the combination of anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage.Methods: this study revealed that BD0801 presents more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). We used the PK profile of BD0801 to guide the subsequent in vivo efficacy studies. Results: BD0801 exhibits dose-dependent tumor growth inhibitory activities in both xenograft and murine syngeneic tumor models. Combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies shows synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Mechanistic studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. The MOA of the antitumor synergy might involve enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells, reduced double-positive CD8+PD-1+ T cells, and improved vasculature normalization. Conclusions: these data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Abstract #827: Panhypopituitarism Due to Immune Checkpoint Inhibitors

2017 ◽  
Vol 23 ◽  
pp. 176-177
Author(s):  
Kaitlyn Steffensmeier ◽  
Bahar Cheema ◽  
Ankur Gupta
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors
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