Improving combination therapies: targeting A2B-adenosine receptor to modulate metabolic tumor microenvironment and
Jason V Evans1,2, Shankar Suman1, Mounika Uttam L Goruganthu1
1Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Background:
We investigated the role of A2B-adenosine receptor in regulating immunosuppressive metabolic stress in the tumor microenvironment. Novel A2B-adenosine receptor antagonist PBF-1129 was tested for antitumor activity in mice and evaluated for safety and immunologic efficacy in a phase I clinical trial of patients with non-small cell lung cancer.
Methods:
The antitumor efficacy of A2B-adenosine receptor antagonists and their impact on the metabolic and immune tumor microenvironment were evaluated in lung, melanoma, colon, breast, and epidermal growth factor receptor-inducible transgenic cancer models. Employing electron paramagnetic resonance, we assessed changes in tumor microenvironment metabolic parameters, including pO2, pH, and inorganic phosphate, during tumor growth and evaluated the immunologic effects of PBF-1129, including its pharmacokinetics, safety, and toxicity, in patients with non-small cell lung cancer.
Results:
Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial inorganic phosphate emerged as a correlative and cumulative measure of tumor microenvironment stress and immunosuppression. A2B-adenosine receptor inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ectonucleotidases, increased expression of adenosine deaminase, decreased tumor growth and metastasis, increased interferon γ production, and enhanced the efficacy of antitumor therapies following combination regimens in animal models (anti-programmed cell death 1 protein vs anti-programmed cell death 1 protein plus PBF-1129 treatment hazard ratio = 11.74 [95% confidence interval = 3.35 to 41.13], n = 10, P < .001, 2-sided F test). In patients with non-small cell lung cancer, PBF-1129 was well tolerated, with no dose-limiting toxicities; demonstrated pharmacologic efficacy; modulated the adenosine generation system; and improved antitumor immunity.
Conclusions:
Data identify A2B-adenosine receptor as a valuable therapeutic target to modify metabolic and immune tumor microenvironment to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.
Insights
Targeting the A2B-adenosine receptor with PBF-1129 reduces tumor immunosuppression and metabolic stress. This approach enhances antitumor immunity and immunotherapy efficacy in preclinical models and early clinical trials for non-small cell lung cancer.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- The tumor microenvironment (TME) exhibits immunosuppressive metabolic stress.
- The A2B-adenosine receptor plays a key role in regulating this immunosuppression.
Purpose of the Study:
- To investigate the role of the A2B-adenosine receptor in TME immunosuppressive metabolic stress.
- To evaluate the antitumor activity, safety, and immunologic efficacy of the novel A2B-adenosine receptor antagonist PBF-1129.
Main Methods:
- Antitumor efficacy of A2B-adenosine receptor antagonists was assessed in various cancer models.
- Metabolic parameters (pO2, pH, inorganic phosphate) in the TME were measured using electron paramagnetic resonance.
- Pharmacokinetics, safety, and toxicity of PBF-1129 were evaluated in a Phase I clinical trial for non-small cell lung cancer.
Main Results:
- Metabolic stress correlated with tumor growth, metastasis, and immunosuppression, with tumor interstitial inorganic phosphate as a key marker.
- A2B-adenosine receptor inhibition alleviated metabolic stress, reduced tumor growth and metastasis, and enhanced interferon-gamma production in animal models.
- PBF-1129 demonstrated good tolerability, pharmacologic efficacy, modulation of the adenosine system, and improved antitumor immunity in non-small cell lung cancer patients.
Conclusions:
- The A2B-adenosine receptor is a viable therapeutic target for modifying the TME's metabolic and immune landscape.
- Inhibiting the A2B-adenosine receptor can reduce immunosuppression and potentiate immunotherapy efficacy.
- PBF-1129 shows promise for clinical application in combination therapies for cancer treatment.
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