Reference Detail

Ref Type

Journal Article

PMID

(27470968)

Authors

Seifert AM, Zeng S, Zhang JQ, Kim TS, Cohen NA, Beckman MJ, Medina BD, Maltbaek JH, Loo JK, Crawley MH, Rossi F, Besmer P, Antonescu CR, DeMatteo RP

Title

PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	2	2017 Jan 15	454-465	Clin Cancer Res

URL

Abstract Text

Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs.We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+ mice that develop GISTs.The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 pos KIT V560del	gastrointestinal stromal tumor	sensitive	Imatinib + unspecified PD-L1 antibody	Preclinical	Actionable	In a preclinical study, the combination of Gleevec (imatinib) and a PD-L1 antibody resulted in a greater decrease in tumor weight and increased apoptotic activity in a gastrointestinal stromal tumor mouse model harboring KIT V558del (corresponds to human KIT V560del) and expressing PD-L1 compared to Gleevec (imatinib) and control (PMID: 27470968).	27470968