The primary purpose of this study is to characterize the safety profile of BMS-986408 as monotherapy and in combination with nivolumab or nivolumab and ipilimumab to establish the maximum tolerated dose (MTD). The Recommended Phase 2 Dose (RP2D) that optimizes the pharmacokinetic/pharmacodynamic (PK/PD) relationship of BMS-986408 will also be determined.

Start Date02 Aug 2022

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with DGKA x DGKζ

100 Translational Medicine associated with DGKA x DGKζ

0 Patents (Medical) associated with DGKA x DGKζ

Literatures (Medical) associated with DGKA x DGKζ

01 Jun 2018·Cancer Immunology, ImmunotherapyQ2 · MEDICINE

Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals

Q2 · MEDICINE

Article

Author: Ogando, Jesús ; Mérida, Isabel ; Meraviglia-Crivelli, Daniel ; Arranz-Nicolás, Javier ; Mañes, Santos ; Arcos-Pérez, Raquel ; Soutar, Denise ; Ávila-Flores, Antonia

The arsenal of cancer therapies has evolved to target T lymphocytes and restore their capacity to destroy tumor cells. T cells rely on diacylglycerol (DAG) to carry out their functions. DAG availability and signaling are regulated by the enzymes diacylglycerol kinase (DGK) α and ζ, whose excess function drives T cells into hyporesponsive states. Targeting DGKα is a promising strategy for coping with cancer; its blockade could reinstate T-cell attack on tumors while limiting tumor growth, due to positive DGKα functions in several oncogenic pathways. Here, we made a side-by-side comparison of the effects of commercial pharmacological DGK inhibitors on T-cell responses with those promoted by DGKα and DGKζ genetic deletion or silencing. We show the specificity for DGKα of DGK inhibitors I and II and the structurally similar compound ritanserin. Inhibitor treatment promoted Ras/ERK (extracellular signal-regulated kinase) signaling and AP-1 (Activator protein-1) transcription, facilitated DGKα membrane localization, reduced the requirement for costimulation, and cooperated with enhanced activation following DGKζ silencing/deletion. DGKiII and ritanserin had similar effects on TCR proximal signaling, but ritanserin counteracted long-term T-cell activation, an effect that was potentiated in DGKα^-/- cells. In contrast with enhanced activation triggered by pharmacological inhibition, DGKα silencing/genetic deletion led to impaired Lck (lymphocyte-specific protein tyrosine kinase) activation and limited costimulation responses. Our results demonstrate that pharmacological inhibition of DGKα downstream of the TCR provides a gain-of-function effect that amplifies the DAG-dependent signaling cascade, an ability that could be exploited therapeutically to reinvigorate T cells to attack tumors.

01 Jan 2008·Frontiers in Bioscience

Nuclear diacylglycerol kinases: regulation and roles

Review

Author: Raben, Daniel M. ; Tu-Sekine, Becky

The diacylglycerol-kinases are a family of related lipid kinases. There are currently 10 known isoforms of diacylglycerol kinases that are categorized into five groups based on similarities in their primary sequence. All of these enzymes catalyze the transfer of the gamma-phosphate of ATP to one lipid second messenger, diacylglycerol, thereby generating another lipid second messenger, phosphatidic acid. As a result, they are uniquely poised to regulate the relative levels of these two key second messengers. These enzymes show considerable diversity in their cellular and sub-cellular distribution which suggests a great diversity in physiological functions. One sub-cellular compartment that is receiving a considerable attention is the nucleus. A number of DGKs have been found to reside in, or translocate to the nucleus in response to agonists. In this review we focus primarily on the nuclear localization, modulation of intrinsic enzymatic activity, and the potential physiological roles of the six diacylglycerol kinases that have been found in the nucleus: DGK-alpha, DGK-gamma, DGK-delta, DGK-zeta, DGK-iota, and DGK-theta.

01 Nov 2006·Nature ImmunologyQ1 · MEDICINE

Disruption of diacylglycerol metabolism impairs the induction of T cell anergy

Q1 · MEDICINE

Article

Author: Jeffery H. Carpenter ; Gary A. Koretzky ; Matthew K. Topham ; Martha Jordan ; Rishu Guo ; Xiao Ping Zhong ; Benjamin A. Olenchock

Anergic T cells have altered diacylglycerol metabolism, but whether that altered metabolism has a causative function in the induction of T cell anergy is not apparent. To test the importance of diacylglycerol metabolism in T cell anergy, we manipulated diacylglycerol kinases (DGKs), which are enzymes that terminate diacylglycerol-dependent signaling. Overexpression of DGK-alpha resulted in a defect in T cell receptor signaling that is characteristic of anergy. We generated DGK-alpha-deficient mice and found that DGK-alpha-deficient T cells had more diacylglycerol-dependent T cell receptor signaling. In vivo anergy induction was impaired in DGK-alpha-deficient mice. When stimulated in anergy-producing conditions, T cells lacking DGK-alpha or DGK-zeta proliferated and produced interleukin 2. Pharmacological inhibition of DGK-alpha activity in DGK-zeta-deficient T cells that received an anergizing stimulus proliferated similarly to wild-type T cells that received CD28 costimulation and prevented anergy induction. Our findings suggest that regulation of diacylglycerol metabolism is critical in determining whether activation or anergy ensues after T cell receptor stimulation.

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