Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc).

Overman, Michael J.; LoRusso, Patricia; Strickler, John H.; Patel, Sandip Pravin; Clarke, Stephen; Noonan, Anne M.; Prasanna, Thiru; Amin, Manik; Nemunaitis, John; Desai, Jayesh; O’Byrne, Kenneth J.; George, Thomas J.; Englert, Judson M.; She, Dewei; Cooper, Zachary A.; Wu, Yuling; Khan, A Nawazish; Kumar, Rakesh; Bendell, Johanna C.

doi:10.1200/jco.2018.36.15_suppl.4123

Cited by 70 publications

(49 citation statements)

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“…In 66 pancreatic or colorectal cancer patients, the αCD73 mAb MEDI9447 as monotherapy and in combination with durvalumab decreased CD73 expression on peripheral T cells. 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: 92%

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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Section: Cd39/cd73mentioning

confidence: 92%

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

Steingold

Hatfield

2020

Front. Immunol.

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“…Moreover, the combination of MEDI9447 with an anti-PD-1 antibody, induces greater antitumor effects as a single agent, supporting the initiation of multiple MEDI9447-based Phase I/II trials. Preliminary Phase I data of MEDI9447 (NCT02503774) were recently reported [138]. Treatment with MEDI9447 and durvalumab (anti-PD-L1) had a manageable safety profile and PD consistent with its mechanism of action.…”

Section: Cd73 In Clinicmentioning

confidence: 99%

Cd73: An Emerging Checkpoint for Cancer Immunotherapy

Chen

Wainwright

et al. 2019

Immunotherapy

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CD73 is a novel immune checkpoint associated with adenosine metabolism that promotes tumor progression by suppressing antitumor immune response and promoting angiogenesis. The inhibition of CD73, in combination with immune checkpoint blockade, targeted therapy or conventional therapy, improves antitumor effects in numerous preclinical mouse models of cancer. Emerging evidence suggests that the combination of anti-CD73 and immune checkpoint blockade has promising clinical activity in patients with advanced solid tumors. In this review, we will discuss the specific role of CD73 on both tumor cells and nontumor cells in regulating tumor immunity and tumorigenesis and provide an update on the current view of the antitumor activity of targeting CD73 by mAb or small molecule selective inhibitors in preclinical and clinical settings.

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“…Allard et al showed that the combination of a CD73 inhibitor with anti-PD1 can increase survival in mice by increasing CD8+ T-cells, since CD73-positive tumor cells are usually resistant to ICI [ 236 ]. Overman et al recently showed promising results with the combination of Durvalumab with Oleclumab (anti-CD73) in pancreatic cancer patients [ 237 ]. Many trials using drug combinations with ICI are underway to try to overcome resistance to ICI.…”

Section: Mechanisms Of Resistance To Immunotherapy and Ways To Ovementioning

confidence: 99%

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

Haibe

Husseini

Sayed

et al. 2020

IJMS

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The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

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Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc).

Cited by 70 publications

References 0 publications

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

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

Cd73: An Emerging Checkpoint for Cancer Immunotherapy

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

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