Cancer Immunotherapy by Targeting A2 Adenosine Receptor

描述（由申请人提供）：本申请修订补充申请的母授权的目的是测试免疫抑制性A2腺苷受体亚型A2 A和A2 B（分别为A2 AR和A2 BR）的遗传失活是否会阻止肿瘤产生的细胞外腺苷抑制抗肿瘤T细胞。预期这将促进小鼠中抗肿瘤T细胞对肿瘤的完全排斥。父母资助是为了确定通过完全消除A2 AR和A2 BR基因来改善抗肿瘤T细胞活性的限度。我们已经证实，基因消除A2 AR而不是A2 BR强烈改善了肿瘤排斥反应。在这项修订后的申请中，我们建议扩大当前资助的范围、目标、设计和方法，并通过药理学灭活A2 AR来使新型癌症免疫疗法更加有效。该提议旨在比较合成和天然A2 AR拮抗剂对癌症疫苗诱导和过继转移的抗肿瘤T细胞活性和肿瘤排斥的影响。这一要求也适合实现复苏法案的目标，因为它导致雇用和留住科学家，学生和动物护理人员，并加速将新颖和有前途的癌症免疫疗法转化为临床治疗。事实上，在我们的初步研究中，我们证明了由于抗肿瘤T细胞与A2 AR拮抗剂的组合而导致的完全肿瘤排斥和存活。这说服了我们和Dana Farber癌症研究所的临床癌症免疫学家，使用现有的癌症免疫治疗方案与A2 AR拮抗剂的组合来准备临床试验。然而，仍有大量的临床前体外和体内实验要做，以更好地了解可能在人体中测试的A2 AR拮抗剂的生物化学、细胞免疫学和药理学作用。因此，我们建议在癌症疫苗和过继免疫治疗的临床前模型中测试不同的选择性合成和天然（例如咖啡因和茶碱）A2 AR拮抗剂。重要的是，开发用于治疗帕金森病的A2 AR拮抗剂KW-6002在III期试验中被发现是安全的，并且在我们的研究中，当与抗肿瘤T细胞组合时，它显示出非常强的抗肿瘤活性。 公共卫生相关性：在这项修订后的申请中，我们建议显着扩大目前拨款的范围，通过阻止肿瘤产生的腺苷抑制抗肿瘤T细胞，使癌症的新型免疫疗法更有效。我们将使用新的合成和天然A2 AR拮抗剂，包括咖啡因和茶碱，以及癌症疫苗诱导或过继转移的抗肿瘤T杀伤细胞。这项研究的结果是雇用和留住科学家，学生和动物护理人员，增加了另一个PI，并加速了新的和有前途的癌症免疫疗法转化为临床治疗。

DESCRIPTION (provided by applicant): The Aims of the parent grant to this requested revision supplement are to test whether genetic inactivation of immunosuppressive A2 adenosine receptor subtypes A2A and A2B (A2AR and A2BR, respectively) will prevent the inhibition of anti-tumor T cells by the tumor-produced extracellular adenosine. This was expected to facilitate the complete rejection of tumors by antitumor T cells in mice. The Parent grant was to determine the limits of improvements of anti-tumor T cell activities by complete elimination of genes for A2AR and A2BR. We have established that the genetic elimination of A2AR-but not of A2BR-strongly improves tumor rejection. In this revised application, we propose to expand the scope, aims, design, and methods of the current grant and render novel immunotherapies of cancer more effective by pharmacologically inactivating A2AR. This proposal is designed to compare the effects of synthetic and natural A2AR antagonists on activities of cancer vaccine-induced and adoptively-transferred anti-tumor T cells and tumor rejection. This request is also appropriate to achieve Recovery Act goals since it results in hiring and retaining scientists, students and animal care workers, adds another PI, and accelerates the translation of novel and promising cancer immunotherapy into clinical therapy. Indeed, in our preliminary studies we demonstrated complete tumor rejection and survival due to the combination of anti-tumor T cells with A2AR antagonist. This convinced us and clinical cancer immunologists at the Dana Farber Cancer Institute to prepare clinical trials using a combination of existing cancer immunotherapy protocols with A2AR antagonists. However, there is still a large body of preclinical in vitro and in vivo experiments to be done in order to develop a better understanding of biochemical, cellular immunological and pharmacological effects of A2AR antagonists likely to be tested in humans. Therefore, we propose to test different selective synthetic and natural (e.g. caffeine and theophylline) A2AR antagonists in preclinical models of cancer vaccines and adoptive immunotherapy. Importantly, the A2AR antagonist KW-6002, developed for treatment of Parkinson Disease, was found to be safe in Phase III trials, and it shows very strong anti-tumor activity in our studies when combined with anti-tumor T cells. PUBLIC HEALTH RELEVANCE: In this revised application, we propose to significantly expand the scope of the current grant to render novel immunotherapies of cancer more effective by pharmacologically preventing the inhibition of anti-tumor T cells by tumor-produced adenosine. We will use novel synthetic and natural A2AR antagonists, including caffeine and theophylline, together with cancer vaccine-induced or with adoptively-transferred anti-tumor T killer cells. This research results in hiring and retaining scientists, students and animal care workers, adds another PI, and accelerates the translation of novel and promising cancer immunotherapy into clinic therapy.