Arginase Therapy Combines Effectively with Immune Checkpoint Blockade or Agonist Anti-OX40 Immunotherapy to Control Tumor Growth

精氨酸酶 癌症研究 免疫疗法 精氨酸 免疫系统 癌症免疫疗法 医学 CD8型 药理学 肿瘤微环境 免疫学 生物 生物化学 氨基酸
作者
Mark Badeaux,Annah S. Rolig,Giulia Agnello,Danlee Enzler,Melissa J. Kasiewicz,Leslie Priddy,Jason F. Wiggins,Alexander Muir,Mark R. Sullivan,Jessica Van Cleef,Christopher Daige,Matthew G. Vander Heiden,Venkatesh Rajamanickam,James E. Wooldridge,William L. Redmond,Scott W. Rowlinson
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:9 (4): 415-429 被引量:37
标识
DOI:10.1158/2326-6066.cir-20-0317
摘要

Abstract Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti–PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer.
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