Abstract CT180:  Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors

Siu, Lillian L.; Burris, Howard A.; Le, Dung T.; Hollebecque, Antoine; Steeghs, Neeltje; Delord, Jean‐Pierre; Hilton, John; Barnhart, Bryan C.; Sega, Emanuela I.; Sanghavi, Kinjal; Klippel, Anke; Hedvat, Cyrus V.; Hilt, Ed; Donovan, Mark; Gipson, Adrianna; Basciano, Paul; Postelnek, Jennifer; Zhao, Yue; Perez, Raymond P.; Carvajal, Richard D.

doi:10.1158/1538-7445.am2018-ct180

Cited by 57 publications

(41 citation statements)

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“…Accordingly, several clinical trials inhibiting CD73 (e.g., antibodies against CD73 or small molecule inhibitors) in combination with ICI therapy, A2AR antagonism, targeted therapy, and/or chemotherapy are underway ( Table 3). Preliminary safety profiles report BMS-986179, an anti-CD73 humanized monocolonal antibody, and its combination with nivolumab (anti-PD-1 therapy) to be well-tolerated in patients (NCT02754141) (251). Recent studies in renal cell cancer (RCC) reported the feasibility and safety of A2AR antagonist, ciforadenant (124).…”

Section: Discussionmentioning

confidence: 99%

“…Future studies in GI cancers that focus on determining if adenosine-mediated resistance to immunotherapy therapy exists at diagnosis or evolves with therapy will also be of significant benefit. Encouraging early results for BMS-986179 combined with nivolumab report clinical benefit (partial response) in one or more patients with pancreatic and prostate cancer (NCT02754141) (251). Both are poorly immunogenic tumors.…”

Section: Discussionmentioning

confidence: 99%

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CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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“…In addition, MEDI9447 decreased CD73 expression in five out of nine tumors, which correlated with increased cytotoxic T cell infiltration (83). The αCD73 mAb BMS986179 as a monotherapy and in combination with the PD-1 inhibitor nivolumab also induced partial responses or stable disease in 17 of 59 patients with various malignancies (84).…”

Section: Cd39/cd73mentioning

confidence: 93%

Targeting Hypoxia-A2A Adenosinergic Immunosuppression of Antitumor T Cells During Cancer Immunotherapy

Steingold

Hatfield

2020

Front. Immunol.

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The blockade of immunological negative regulators offered a novel therapeutic approach that revolutionized the immunotherapy of cancer. Still, a significant portion of patients fail to respond to anti-PD-1/PD-L1 and/or anti-CTLA-4 therapy or experience significant adverse effects. We propose that one of the major reasons that many patients do not respond to this form of therapy is due to the powerful physiological suppression mediated by hypoxia-adenosinergic signaling. Indeed, both inflamed and cancerous tissues are hypoxic and rich in extracellular adenosine, in part due to stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). Adenosine signals through adenosine A2A receptors (A2AR) to suppress anti-tumor and anti-pathogen immune responses. Several classes of anti-hypoxia-A2AR therapeutics have been offered to refractory cancer patients, with A2AR blockers, inhibitors of adenosine-generating enzymes such as CD39 and CD73, and hypoxia-targeting drugs now reaching the clinical stage. Clinical results have confirmed preclinical observations that blockade of the hypoxia-adenosine-A2AR axis synergizes with inhibitors of immune checkpoints to induce tumor rejection. Thus, A2AR blockers provide a new hope for the majority of patients who are nonresponsive to current immunotherapeutic approaches including checkpoint blockade. Here, we discuss the discoveries that firmly implicate the A2AR as a critical and non-redundant biochemical negative regulator of the immune response and highlight the importance of targeting the hypoxia-adenosine-A2AR axis to manipulate anti-pathogen and anti-tumor immune responses.

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“…Practical approaches to target the adenosinergic pathway and adenosine A 2A receptor signaling CD39 inhibits the immune system by degrading ATP into AMP, which is then further degraded into adenosine by CD73. In the last decade, CD73, CD39, and A 2A R receptors' potential as immunotherapy targets for cancer and microbial infections have rapidly increased [17][18][19][20][21][22]. Humanized monoclonal anti-CD39, such as IPH5201 (Innate Pharma), have been developed [23].…”

Section: Ectonucleotidases and Adenosine Receptor Activity Promote Immentioning

confidence: 99%

Targeting adenosinergic pathway and adenosine A2A receptor signaling for the treatment of COVID-19: A hypothesis

Abouelkhair

2020

Medical Hypotheses

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Abstract CT180: Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors

Cited by 57 publications

References 0 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Targeting Hypoxia-A2A Adenosinergic Immunosuppression of Antitumor T Cells During Cancer Immunotherapy

Targeting adenosinergic pathway and adenosine A2A receptor signaling for the treatment of COVID-19: A hypothesis

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