Targeting CD73 in the tumor microenvironment with MEDI9447

Abstract

MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. Changes include significant alterations in a number of tumor micro-environmental subpopulations including increases in CD8+ effector cells and activated macrophages. Furthermore, these changes correlate directly with responder and non-responder subpopulations within animal studies using syngeneic tumors. Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).

Anti-CD73 immunotherapy: A viable way to reprogram the tumor microenvironment

“…Interestingly, the pharmacological blockade of CD73 with MEDI9447 was associated with increased antigen presentation and enhanced lymphocyte activation, resulting in a greater release of proinflammatory Th 1 cytokines (IFNg, IL-1b, and TNF). 7 Moreover, when testing the in vivo effects of MEDI9447, the authors observed an inhibition of syngeneic tumor growth. 7 At odds with the other cancer immunotherapies, such as checkpoint inhibitors or T cell agonists, MEDI9447 was found to shape the composition of both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment.…”

“…7 Moreover, when testing the in vivo effects of MEDI9447, the authors observed an inhibition of syngeneic tumor growth. 7 At odds with the other cancer immunotherapies, such as checkpoint inhibitors or T cell agonists, MEDI9447 was found to shape the composition of both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment. 7 In particular, the blockade of CD73 with MEDI9447 increased the infiltration of several immune cell populations, such as CD8 + effector cells and activated macrophages, into the cancer niche.…”

“…6 In addition, the efficacy of MEDI9447 in inhibiting CD73 does not require the blockade of multiple substrates at level of the active site. 6 The study by Hay et al, 7 published in the present issue of OncoImmunology, points out the wide-ranging role of CD73-derived adenosine on the phenotype of both lymphoid and myeloid-derived cells, shaping both the innate and adaptive arms of antitumor immunity. In this study, in vitro experiments documented the efficacy of MEDI9447 in reversing adenosine-mediated CD4 + T cell suppression.…”

“…7 At odds with the other cancer immunotherapies, such as checkpoint inhibitors or T cell agonists, MEDI9447 was found to shape the composition of both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment. 7 In particular, the blockade of CD73 with MEDI9447 increased the infiltration of several immune cell populations, such as CD8 + effector cells and activated macrophages, into the cancer niche. 7 In parallel, MEDI9447 revealed a synergic activity upon its combined administration with anti-PD-1 antibodies, further supporting the potential value of relieving adenosine-mediated immunosuppression.…”

“…7 In particular, the blockade of CD73 with MEDI9447 increased the infiltration of several immune cell populations, such as CD8 + effector cells and activated macrophages, into the cancer niche. 7 In parallel, MEDI9447 revealed a synergic activity upon its combined administration with anti-PD-1 antibodies, further supporting the potential value of relieving adenosine-mediated immunosuppression. 7 Over the years, epidemiological observations have indicated that overfeeding and obesity represent negative prognostic factors with regard to the incidence, progression, and therapeutic response of several neoplasias.…”