Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

BackgroundAryl Hydrocarbon Receptor (AHR) is a transcription factor that regulates the activity of multiple innate and adaptive immune cells subsequent to binding to a diverse set of endogenous and exogenous ligands. One such endogenous AHR ligand is kynurenine, generated from the precursor tryptophan by indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). Binding of kynurenine to AHR leads to a net immunosuppressive tumor microenvironment. In addition, increased levels of serum kynurenine are associated with resistance to checkpoint inhibitors. Given that kynurenine can be generated by both IDO1 and TDO2 and that AHR is activated by multiple other endogenous ligands, AHR inhibition provides a novel and ideal approach to overcome immunosuppression in a broad range of cancers.MethodsWe sought to identify an orally active AHR antagonist as an immunomodulatory agent for the treatment of solid tumors. Lead optimization efforts identified IK-175 as an AHR antagonist with a favorable ADME and pharmacokinetic profile in preclinical species.ResultsIK-175 inhibits AHR activity in rodent and human cancer cell lines as well as human and nonhuman primate primary immune cells, with concentration dependent effects on AHR target gene expression and cytokine release. IK-175 is inactive in a broad panel of kinases, receptors, and transporters. Orally administered IK-175 dose-dependently blocks ligand stimulated-AHR activation of Cyp1a1 transcription in liver and spleen, demonstrating on-target in vivo activity in mice. IK-175 alone and in combination with an anti-PD-1 antibody demonstrates significant antitumor activity in syngeneic mouse models of colorectal cancer (CT26.WT) and melanoma (B16-IDO1). In addition, IK-175 in combination with liposomal doxorubicin demonstrates antitumor activity in syngeneic mouse models of colorectal cancer (CT26.WT and MC38).ConclusionsThese studies provide rationale for targeting AHR in cancer patients. Ikena will evaluate the anti-tumor activity of IK-175 as a single agent in cancers with activated AHR and in combination with other therapies. Overall, our data demonstrates that IK-175 is a selective orally active AHR antagonist that inhibits tumor growth and reverses immune suppression in mouse tumors models. IK-175 is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors and urothelial carcinoma (Clinicaltrials.gov NCT04200963).

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Immunophenotyping, RNAseq, microbiota analysis of syngeneic mouse models treated with immune checkpoint inhibitors to support biomarker and immune-oncology drug discovery

European Journal of Cancer ◽

10.1016/s0959-8049(16)32919-7 ◽

2016 ◽

Vol 69 ◽

pp. S108

Author(s):

L. Zhang ◽

M. Qiao ◽

J. Zhang ◽

S. Guo ◽

W. Qian ◽

...

Keyword(s):

Drug Discovery ◽

Mouse Models ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Syngeneic Mouse ◽

Oncology Drug ◽

Microbiota Analysis ◽

Immune Oncology

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OC-0282 Inhibition of oxidative phosphorylation alters the tumor microenvironment in syngeneic mouse models

Radiotherapy and Oncology ◽

10.1016/s0167-8140(21)06832-8 ◽

2021 ◽

Vol 161 ◽

pp. S191-S192

Author(s):

D. Boreel ◽

P. Span ◽

A. Kip ◽

H. Peters ◽

R. van den Bijgaart ◽

...

Keyword(s):

Tumor Microenvironment ◽

Oxidative Phosphorylation ◽

Mouse Models ◽

Syngeneic Mouse

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A Novel Chemical Attack on Notch-mediated transcription by targeting the NACK ATPase

10.21203/rs.3.rs-733100/v1 ◽

2021 ◽

Author(s):

G. Diluvio ◽

T. T. Kelley ◽

M. Lahiry ◽

A. Alvarez Trotta ◽

E. M. Kolb ◽

...

Keyword(s):

Antitumor Activity ◽

Mouse Models ◽

Small Molecule ◽

Ternary Complex ◽

Small Molecule Inhibitor ◽

Chemical Attack ◽

Dependent Function ◽

Molecule Inhibitor ◽

Efficacious Treatment ◽

Notch Activation

Abstract Notch Activation Complex Kinase, NACK, is a component of the Notch transcriptional machinery critical to Notch-mediated tumorigenesis. However, the mechanism by which NACK regulates the Notch-mediated transcription is not well understood. Here we demonstrate that NACK binds and hydrolyses ATP and that only ATP-bound NACK is able to bind to the Notch Ternary Complex (NTC). Considering this we sought to identify inhibitors of this ATP-Dependent function and, using computational pipelines, discovered the first small molecule inhibitor of NACK, Z271-0326, that directly blocks the activity of Notch-mediated transcription and shows potent antitumor activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for efficacious treatment of Notch-driven cancers by blocking the Notch downstream NTC activity.

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SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

Science Translational Medicine ◽

10.1126/scitranslmed.abd8836 ◽

2021 ◽

Vol 13 (591) ◽

pp. eabd8836

Author(s):

Axel Hyrenius-Wittsten ◽

Yang Su ◽

Minhee Park ◽

Julie M. Garcia ◽

Josef Alavi ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

T Cell ◽

Antitumor Activity ◽

Solid Tumors ◽

Mouse Models ◽

Solid Tumor ◽

Car T Cells ◽

Therapeutic Benefits ◽

Car T

The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.

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Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.9b00946 ◽

2019 ◽

Vol 62 (18) ◽

pp. 8557-8577 ◽

Cited By ~ 17

Author(s):

Sida Shen ◽

Melissa Hadley ◽

Kseniya Ustinova ◽

Jiri Pavlicek ◽

Tessa Knox ◽

...

Keyword(s):

Antitumor Activity ◽

Histone Deacetylase ◽

Mouse Models ◽

Histone Deacetylase 6

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SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers11081151 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1151 ◽

Cited By ~ 4

Author(s):

Sara Gomes ◽

Bartolomeo Bosco ◽

Joana B. Loureiro ◽

Helena Ramos ◽

Liliana Raimundo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Antitumor Activity ◽

Tumor Cells ◽

Mouse Models ◽

Anticancer Agents ◽

Human Tumor ◽

Endoplasmic Reticulum Stress Response ◽

Mutant P53 ◽

Wild Type ◽

Proliferative Effect

Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

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