A Phase 1/2 Dose Escalation and Combination Cohort Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Efficacy of BMS-986226 Alone or in Combination With Nivolumab or Ipilimumab in Patients With Advanced Solid Tumors

The purpose of this study is to investigate BMS-986226 administered alone or in combination with nivolumab or ipilimumab.

Start Date01 Sep 2017

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with Anti-ICOS(Bristol Myers Squibb Co.)

100 Translational Medicine associated with Anti-ICOS(Bristol Myers Squibb Co.)

100 Patents (Medical) associated with Anti-ICOS(Bristol Myers Squibb Co.)

Literatures (Medical) associated with Anti-ICOS(Bristol Myers Squibb Co.)

01 Aug 2023·Cancer research communications

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

Article

Author: Liu, Yao-Bin ; Paul, Elaine ; Grant, Steven ; Gagnon, Robert ; Maio, Michele ; Waight, Jeremy D ; Rischin, Danny ; Hopson, Christopher B ; Chisamore, Michael ; Fieles, William ; Jing, Junping ; Yadavilli, Sapna ; DeYoung, M Phillip ; Mayes, Patrick A ; Srinivasan, Roopa ; Shaik, Jafar Sadik ; Biddlecombe, Robert ; Figueroa, David J ; Shi, Hong ; Seestaller-Wehr, Laura ; Brett, Sara ; Olive, Daniel ; Ballas, Marc ; Hoos, Axel ; Ellis, Catherine ; Hook, Laura ; Hahn, Ashleigh ; Bi, Meixia ; Blackwell, Christina ; Turner, David C ; Xie, Qing ; Smothers, James ; Hopley, Stephanie ; Zhang, Tianqian ; Ji, Xiao

In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies.SignificanceStimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

01 Oct 2017·VaccineQ3 · MEDICINE

Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer

Q3 · MEDICINE

Article

Author: Shi, Xiaojun ; Mo, Lijun ; Chen, Qianmei ; Wei, Lili ; Zheng, Dianpeng ; Li, Jinlong ; Hu, Zhiming ; Gao, Jimin ; Li, Hongwei ; Zhang, Xinji

ICOS⁺Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS⁺Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8⁺ and CD4⁺T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS⁺Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone.

01 Oct 2012·Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology

[Influence of anti-ICOS antibody on quantity and function of CD4(+);CD25(+);Foxp3(+);Treg from lymph and blood of rats with bronchial asthma].

Article

Author: Wang, Yue-si ; Feng, Xue-bin ; Cao, Yin-yin ; Zhao, Lei ; Cui, Qing-qing

AIMTo investigate the influences of anti-ICOS antibody (anti-ICOSAb) on quantity and function of CD4(+);CD25(+);Foxp3(+);Treg cells from lymph and peripheral blood of rats with bronchial asthma.METHODSThe mononuclear cells (MNC) from lymph and blood were co-cultured with anti-ICOSAb, and then the percentage of CD4(+);CD25(+);Foxp3(+);Treg cells were analyzed by flow cytometer (FCM) and the levels of IL-10 and TGF-β1 in supernatants were determined by ELISA.RESULTSThe MNC were collected from lymph and blood at 0, 24 and 48 h after the last challenge, respectively, and the cells were cultured for 96 h in vitro. The percentage of CD4(+);CD25(+);Foxp3(+);Treg cells in the MNC from lymph was significantly higher than that from blood in each group (P<0.05); The percentage of CD4(+);CD25(+);Foxp3(+);Treg cells in the MNC from lymph and blood in asthma group was significantly lower compare with the normal control group (P<0.05); The percentage of CD4(+);CD25(+);Foxp3(+);Treg cells in the MNC from lymph and blood in the anti-ICOSAb group obviously decreased compare with the asthma group (P<0.05). At 0 h after the last challenge, the level of IL-10 in the supernatant of MNC from lymph and blood in the anti-ICOSAb group were significantly lower than that of the control and asthma groups (P<0.05), while there were no significant differences of TGF-β1 expression in the supernatant of MNC from lymph and blood in each group at different time points.CONCLUSIONBlocking the ICOS/ICOSL signaling pathway by anti-ICOSAb could exacerbate the deficiency of CD4(+);CD25(+);Foxp3(+);Treg cells from lymph and blood in bronchial asthmatic rat, meanwhile inhibit the CD4(+);CD25(+);Foxp3(+);Treg cells secreting IL-10 at 0 h after the last challenge, but have no significant effect on the secretion of TGF-β1.

100 Deals associated with Anti-ICOS(Bristol Myers Squibb Co.)

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	Spain	Bristol Myers Squibb Co.	01 Sep 2017
Advanced Malignant Solid Neoplasm	Phase 2	United States	Bristol Myers Squibb Co.	01 Sep 2017
Advanced Malignant Solid Neoplasm	Phase 2	Switzerland	Bristol Myers Squibb Co.	01 Sep 2017
Advanced Malignant Solid Neoplasm	Phase 2	Canada	Bristol Myers Squibb Co.	01 Sep 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03251924 (CTgov)	Phase 1/2	Advanced Malignant Solid Neoplasm	80	BMS-986226 (Preliminary - BMS-986226 2 mg)	ftllpqdpum(eolxfmjclr) = mfgndhgwxd cizrmofqyh (xycitbcyzj, cgtoflgvdr - mnyucdornd) View more	-	28 Feb 2023
				BMS-986226 (Preliminary - BMS-986226 8 mg)	ftllpqdpum(eolxfmjclr) = onnsjiwoga cizrmofqyh (xycitbcyzj, aydzcotopw - oshcktofhl) View more

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