Delving into the Latest Updates on BMS-687681 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CCR2 x CCR5

Action

antagonists

Mechanism

CCR2 antagonists(C-C chemokine receptor type 2 antagonists), CCR5 antagonists(C-C chemokine receptor type 5 antagonists)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Bristol Myers Squibb Co.

License Organization-

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Author: Niu, Nan ; Zlomke, Haley ; Ding, Ding ; He, Jin ; Fu, Juan ; Xu, Yao ; Muth, Stephen ; Zheng, Lei ; Wang, Junke ; Chen, Sophia ; Twyman-Saint Victor, Christina ; Saung, May Tun ; Funes, Vanessa ; Rozich, Noah ; Espinoza, Birginia ; Wang, Jianxin ; Henderson, MacKenzie ; Narang, Amol ; Fujiwara, Kenji ; Li, Keyu ; Zhao, Qihong ; Herbst, Brian

The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti–PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor–associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.

100 Deals associated with BMS-687681

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