Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors

Fatima, Zainab; Abonofal, Abdulrahman; Stephen, Bettzy

doi:10.36401/jipo-22-27

Cited by 4 publications

(3 citation statements)

References 111 publications

(131 reference statements)

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“…[14][15][16][17] Given the immunosuppressive effect of arginase, arginase pharmacological inhibition can be a compelling strategy for cancer immunotherapy. 18 Because arginase participates in the urea cycle to dispose of toxic ammonia, a potential toxicity of concern for arginase inhibitors is disruption of the urea cycle in the liver and subsequent hyperammonaemia. 19 Detection of high orotic acid levels in urine is a sensitive indication of urea cycle disruption: when arginase fails its role in the urea cycle, a metabolic diversion into the pyrimidine synthesis pathway results in buildup of the pyrimidine precursor orotic acid.…”

Section: What This Study Addsmentioning

confidence: 99%

First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours

Naing,

Papadopoulos,

Pishvaian

et al. 2024

bmjonc

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ObjectiveThe arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.Methods and analysisIn this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti−PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).ResultsA total of 107 patients received INCB001158 50–150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50–100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti–PD-1/PD-L1–naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.ConclusionsINCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.Trial registration numberNCT02903914.

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Section: What This Study Addsmentioning

confidence: 99%

First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours

Naing,

Papadopoulos,

Pishvaian

et al. 2024

bmjonc

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“…Increased fatty acid production and elevated glutamine metabolism are just two examples of tumors’ unusual metabolic features [ 174 , 175 ]. Cancer cells, in contrast to normal cells, which typically rely on growth factor signaling to make use of energy resources [ 176 ], break down these resources via glycolysis and glutaminolysis to divert the intermediate products that are required for biosynthetic pathways and the maintenance of cellular growth and proliferation [ 177 ]. As a result of this metabolic transition, cells are no longer limited in their ability to grow and divide.…”

Section: Approaches To Overcome Drug Resistancementioning

confidence: 99%

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

Farhan

2023

Biomedicines

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Chemotherapy resistance is still a serious problem in the treatment of most cancers. Many cellular and molecular mechanisms contribute to both inherent and acquired drug resistance. They include the use of unaffected growth-signaling pathways, changes in the tumor microenvironment, and the active transport of medicines out of the cell. The antioxidant capacity of polyphenols and their potential to inhibit the activation of procarcinogens, cancer cell proliferation, metastasis, and angiogenesis, as well as to promote the inhibition or downregulation of active drug efflux transporters, have been linked to a reduced risk of cancer in epidemiological studies. Polyphenols also have the ability to alter immunological responses and inflammatory cascades, as well as trigger apoptosis in cancer cells. The discovery of the relationship between abnormal growth signaling and metabolic dysfunction in cancer cells highlights the importance of further investigating the effects of dietary polyphenols, including their ability to boost the efficacy of chemotherapy and avoid multidrug resistance (MDR). Here, it is summarized what is known regarding the effectiveness of natural polyphenolic compounds in counteracting the resistance that might develop to cancer drugs as a result of a variety of different mechanisms.

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“…In TME, CD39 and CD73 ectonucleotidase are expressed not only on cancer cells but also on various immune cells such as regulatory T cells, tumor associated macrophages, tolerogenic DCs that contribute to immune regulation [25][26] [27],the inhibition of these ectonucleotidase has shown a reduced tumor growth in different mouse models [26][28]. The combinational immunotherapy targeting metabolic checkpoint (ectonucleotidase) and immune checkpoint (PDL1-PD1) have shown a promising reduction in tumor growth of colon cancer model [29] [30] [31].…”

Section: Introductionmentioning

confidence: 99%

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

DALAI,

Shah,

Soni

et al. 2024

Preprint

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Purpose Studies have reported that cellular metabolism at tumor-immune microenvironment (TiME) serve as a critical checkpoint and perturbs/supports anti-cancer immunity. Extracellular ATP (eATP) may mediate anti-cancer immune response however; its catabolism by ectonucleotidase generates immunosuppressive adenosine. Antagonist of ectonucleotidases: CD39 and CD73 have been explored as potential therapeutic. In the presented work we have tried to repurpose doxycycline for mitigating ATP metabolism with or without antagonist of ectonucleotidase. Methods eATP and adenosine level were quantified. The bone marrow-derived M1 and M2 polarized macrophages were maintained in tumor mimicking condition (TMC). Total or CD4+ Tcells were co-cultured with macrophages to understand the impact of doxycycline and antagonist of ectonucleotidase T cell/subset differentiation. Preclinical efficacy of doxycycline and ectonucleotidase antagonist and their synergy was scored in 4T1 breast carcinoma. Results Doxycycline manipulates macrophage polarization by decreasing the frequency CD206+M2 macrophages that promoted CD4+ directed CD8+ T cell mediated tumor cell lysis. Doxycycline alleviated the expression of CD39 and CD73, rescuing ATP catabolism. Doxycycline delayed tumor growth by enhancing F4/80+ CD86+ M1 macrophages and subsequently anti-tumor Tbet+ CD4+ T-cells, attenuating the frequency of FOXP3+ regulatory T cells which was cooperatively supported by ARL67156 and AMPCP (CD39 and CD73 antagonist). Doxycycline promoted CD8+T cell mediated cytotoxicity which was synergistically enhanced with ARL67156 and AMPCP ensuring a possibility of using doxycycline alone or in combination with antagonist of ectonucleotidase. Conclusion Presented data indicate a prospective usage of doxycycline as novel immune checkpoint blocker (ICB) against ectonucleotidase and may be modified/delivered appropriately as a sole ICB.

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Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors

Cited by 4 publications

References 111 publications

First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours

First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

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