Response-Adaptive Surgical Timing in Neoadjuvant Immunotherapy Demonstrates Enhanced Pathologic Treatment Response in Head and Neck Squamous Cell Carcinoma

Article

Author: Scher, Jessica ; Scott, E. Reilly ; Alnemri, Angela ; Linnenbach, Alban J. ; Mahoney, My G. ; Tekumalla, Sruti ; Argiris, Athanassios ; Nunes, Kathryn L. ; Luginbuhl, Adam J. ; Jegede, Victor ; Llerena, Pablo ; Seim, Nolan ; Zhan, Tingting ; South, Andrew P. ; Mann, Derek ; Prendergast, George ; Henao, Camilo ; Tuluc, Madalina ; Kushnarev, Vladimir ; Gargano, Stacey ; Axelrod, Rita ; Chasse, Madison ; Old, Matthew ; Davitt, Christopher J.H. ; Nikitina, Anastasia ; Sookiasian, Danielle ; Curry, Joseph M. ; Mastrolonardo, Eric V. ; Harshyne, Larry A. ; Cognetti, David M. ; Leiby, Benjamin E. ; Sobol, Anastasia ; Johnson, Jennifer M. ; Martinez-Outschoorn, Ubaldo ; Tyshevich, Andrey

AbstractPurpose:We evaluated whether indoleamine 2,3-dioxygenase (IDO1) inhibitor (IDOi) BMS986205 + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable head and neck squamous cell carcinoma (HNSCC). We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response.Patients and Methods:Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 orally daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by human papillomavirus (HPV) status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after treatment with nivolumab in both arms. Nonresponders underwent surgical resection, whereas responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing.Results:Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (P = 0.909). Treatment was well tolerated, with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDOi augmented rates of pTR in patients with high baseline IDO1 RNA expression (P < 0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus nonresponders (P = 0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-γ expression in the HPV− cohort correlated with response. The HPV+ cohort found B-cell and cancer-associated fibroblast signatures predictive of response/nonresponse.Conclusions:Response-adaptive surgical timing enhanced treatment response. IDOi BMS986205 augmented pTR in patients with high IDO1 expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV status–dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

24 Dec 2024·Proceedings of the National Academy of Sciences

Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response

Article

Author: Shi, Xiaolin ; Xu, Jialu ; Yao, Chenlu ; Tian, Bo ; Xu, Fang ; Wu, Bingbing ; Dai, Huaxing ; Wang, Heng ; Wang, Chao

Inhibiting indoleamine 2,3 dioxygenase (IDO) for anticancer therapy has garnered significant attention in recent years. However, current IDO inhibitors face significant challenges which limit their clinical application. Here, we genetically engineered a high tryptophan-expressing Clostridium butyricum (L-Trp CB) strain that can colonize tumors strictly following systemic administration. We revealed that butyrate produced by L-Trp CB can inhibit IDO activity, preventing tryptophan catabolism and kynurenine accumulation in tumors. In addition, the large released tryptophan by L-Trp CB can provide discrete signals that support CD8+ T cell activation and energy metabolism within the tumor microenvironment. We observed that L-Trp CB significantly restored the proportion and function of CD8+ T cells, leading to significantly delayed tumor growth in both mouse and rabbit multiple tumor models with limited side effects. We here provide a synthetic biology treatment strategy for enhanced tumor immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response in tumors.

01 Dec 2024·Blood Research

Increased IDO expression and regulatory T cells in acute myeloid leukemia: implications for immune escape and therapeutic targeting

Article

Author: Poopak, Behzad ; Hakak, Raziyeh ; Majd, Ahmad

AbstractPurposeThis study aimed to determine the frequency of regulatory T cells (Tregs) (CD4+/FOXP3+) and indoleamine 2,3-dioxygenase (IDO) expression in patients with acute myeloid leukemia (AML).MethodsThis cross-sectional case–control study was conducted between Jan 2022 and Dec 2023. Bone marrow samples were collected from 20 healthy individuals and 15 patients with AML. Flow cytometry, real-time polymerase chain reaction (PCR), and western blotting were used to evaluate the frequency of Treg and IDO expression levels.ResultsThe Treg percentage among total lymphocytes was lower in the AML group than that in the normal group. However, Treg percentage among T-helper (Th) lymphocytes was significantly higher in the AML group than that in the normal group (p < 0.05). The mean IDO expression in the AML group was significantly higher than that in the normal group (p = 0.004). A significant relationship was observed between IDO expression and Treg percentage among Th lymphocytes in the AML group (correlation = 0.637; p = 0.003). Moreover, western blot analysis showed a significant increase in IDO protein intensity in the AML group compared with that in the control group (p < 0.001). A significant difference was observed between the IDO concentrations in the AML group and that in the control group (p < 0.001). In addition, a significant difference between TGF-β levels in the AML group and those in the control group (p < 0.01) was observed.ConclusionIDO inhibition using novel IDO inhibitors along with chemotherapy is a promising approach to overcome the immune escape mechanisms in patients with AML, who exhibit increased levels of IDO expression and Tregs.

100 Deals associated with IDO Inhibitor (Qilu Pharm)

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Immune System Diseases	Preclinical	China	Qilu Pharmaceutical Co., Ltd.	25 Dec 2020
Infectious Diseases	Preclinical	China	Qilu Pharmaceutical Co., Ltd.	25 Dec 2020
Inflammation	Preclinical	China	Qilu Pharmaceutical Co., Ltd.	25 Dec 2020
Neoplasms	Preclinical	China	Qilu Pharmaceutical Co., Ltd.	25 Dec 2020

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

IDO Inhibitor (Qilu Pharm)

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation