Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours

Naing, Aung; Bauer, Todd M.; Papadopoulos, K.; Rahma, Osama E.; Tsai, Frank; Garralda, Elena; Naidoo, Jarushka; Pai, Sachin; Gibson, Michael K.; Rybkin, Igor I.; Wang, D.; McDermott, David F.; Fasolo, Angelica; Miguel, Marı́a de; Shaheen, Monte; Jenkins, Yonchu; Kallender, Howard; Gogov, Sven; Kuriakose, Emil; Pishvaian, Michael J.

doi:10.1093/annonc/mdz244.002

Cited by 30 publications

(31 citation statements)

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“…In microsatellite stable (MSS) colorectal cancer patients involved in this study, 7 and 6% of partial responses to the INCB001158 and pembrolizumab (anti-PD1 monoclonal antibody) combination or INCB001158 monotherapy, respectively, were reported. Importantly, objective pharmacodynamic parameters such as an increase in the intratumoral CD8 + T-cells as well as dose-related increase in plasma L-arg were achieved in the treated individuals (283).…”

Section: Arginase Inhibitorsmentioning

confidence: 97%

Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

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Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

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Section: Arginase Inhibitorsmentioning

confidence: 97%

Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

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“…In this study, patients will be randomized to platinum-fluorouracilpembrolizumab plus GSK3359609 or placebo (NCT04428333). In addition to the aforementioned phase 3 studies, multiple phase 1/2 clinical trials with PD-1/PD-L1 inhibitors combined with a second drug targeting a variety of pathways are ongoing or have been completed ( Table 1) (170)(171)(172)(173)(174)(175)(176)(177)(178)(179)(180)(181)(182)(183)(184)(185)(186)(187). Studies for which data have been reported are summarized in Table 1.…”

Section: Programmed Death-1 Inhibitor Plus Lenvatinibmentioning

confidence: 99%

Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas

2021

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Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.

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“…The arginase inhibitor CB-1158 [ 178 ] ( Figure 5 ), developed by Calithera Bioscience Inc., has been evaluated for the therapeutic blockade of immunosuppressive cells in the tumor microenvironment [ 179 ] and is currently undergoing clinical evaluation in patients with solid tumors [ 180 ]. The same biopharmaceutical company developed a novel orally dosed arginase inhibitor CB-280 (undisclosed structure), which already entered phase I trials for the treatment of cystic fibrosis [ 181 ].…”

Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

Clemente

Waarde

Antunes

et al. 2020

IJMS

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Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

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Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours

Cited by 30 publications

References 0 publications

Myeloid Cell-Derived Arginase in Cancer Immune Response

Myeloid Cell-Derived Arginase in Cancer Immune Response

Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

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