Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors

Wang, Lin; Londono, Luz M.; Cowell, Jessica; Saatçi, Özge; Aras, Mertkaya; Ersan, Pelin G.; Serra, Sara; Pei, Hong; Clift, Renee; Zhao, Qiping; Phan, Kim B.; Huang, Lei; LaBarre, Michael J.; Li, Xiaoming; Shepard, H. Michael; Deaglio, Silvia; Linden, Joel; Thanos, Christopher D.; Şahin, Özgür; Cekic, Caglar

doi:10.1158/0008-5472.can-21-0340

Cited by 24 publications

(18 citation statements)

References 62 publications

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“…Both recombinant ADA protein and the viral vectored ADA gene are approved in enzyme replacement therapy (ERT) for the treatment of adenosine deaminase deficiencybased severe combined immunodeficiency (SCID), representing an excellent precedent for a favorable safety profile of the ADA enzyme [72,73]. Although the use of ADA in cancer therapy might seem obvious, only recently has a PEGylated ADA2 (PEGADA2) been investigated in preclinical cancer models revealing promising results for clinical translation [74]. While the human genome encodes two different adenosine deaminases (ADA1 and ADA2), only ADA1 orthologue has been characterized in mice.…”

Section: Discussionmentioning

confidence: 99%

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

Gentile

Finizio

Froechlich

et al. 2021

IJMS

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Background: Oncolytic viruses are immunotherapeutic agents that can be engineered to encode payloads of interest within the tumor microenvironment to enhance therapeutic efficacy. Their therapeutic potential could be limited by many avenues for immune evasion exerted by the tumor. One such is mediated by adenosine, which induces pleiotropic immunosuppression by inhibiting antitumor immune populations as well as activating tolerogenic stimuli. Adenosine is produced starting from the highly immunostimulatory ATP, which is progressively hydrolyzed to ADP and adenosine by CD39 and CD73. Cancer cells express high levels of CD39 and CD73 ectoenzymes, thus converting immunostimulatory purinergic signal of ATP into an immunosuppressive signal. For this reason, CD39, CD73 and adenosine receptors are currently investigated in clinical trials as targets for metabolic cancer immunotherapy. This is of particular relevance in the context of oncovirotherapy, as immunogenic cell death induced by oncolytic viruses causes the secretion of a high amount of ATP which is available to be quickly converted into adenosine. Methods: Here, we took advantage of adenosine deaminase enzyme that naturally converts adenosine into the corresponding inosine derivative, devoid of immunoregulatory function. We encoded ADA into an oncolytic targeted herpes virus redirected to human HER2. An engineered ADA with an ectopic signal peptide was also generated to improve enzyme secretion (ADA-SP). Results: Insertion of the expression cassette was not detrimental for viral yield and cancer cell cytotoxicity. The THV_ADA and THV_ADA-SP successfully mediated the secretion of functional ADA enzyme. In in vitro model of human monocytes THP1, this ability of THV_ADA and THV_ADA-SP resulted in the retrieval of eADO-exposed monocytes replication rate, suggesting the proficiency of the viruses in rescuing the immune function. Conclusions: Encoding ADA into oncolytic viruses revealed promising properties for preclinical exploitation.

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Section: Discussionmentioning

confidence: 99%

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

Gentile

Finizio

Froechlich

et al. 2021

IJMS

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“…PEGylated ADA2 was shown to stimulate T cell proliferation, promote tumor infiltration, and inhibit tumor growth in both colon and breast cancer murine models. 55 …”

Section: Preclinical Investigationmentioning

confidence: 99%

Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy

Augustin

Leone

Naing

et al. 2022

J Immunother Cancer

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Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.

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“…Recently, PEGylated ADA2 (PEGADA2) was studied on preclinical cancer models, providing promising results for clinical application [109]. In mice, PEGADA2 inhibited tumor growth depending on the level of the enzyme activity and affected the immune response.…”

Section: Targeting Adk and Ada In The Cancer Therapymentioning

confidence: 99%

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

et al. 2022

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The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5′-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.

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Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors

Cited by 24 publications

References 62 publications

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

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