Human mast cells as a platform for new cancer immunotherapy strategies

摘要 人类组织肥大细胞(MC)在许多癌症的病理中的作用尚不清楚。中国的相关研究 人类已经发现，肿瘤微环境中的高MC数具有促肿瘤和抗肿瘤的作用， 根据癌症类型对比患者的结果。我们发现人类的MC被激活， 并在体外和体内促进对癌细胞的杀伤，渗透实体细胞瘤块，与体内肿瘤结合， 可以获得患者输液所需的数量，在不损失功能的情况下进行冷冻保存和展示 静脉注射给移植了人类肿瘤的小鼠，没有明显的毒性作用。为了发展这部小说， 基于细胞的癌症免疫治疗我们将使用美国食品和药物管理局批准的人源化IgE(它将MC FCεRI与 极高的亲和力)将MC靶向癌细胞。这种新方法的前提是高效的、自体的 MC的产生、肿瘤靶向和有效的肿瘤特异性杀伤。这一战略并不可行。 到目前为止，因为这些细胞驻留在组织中，不能获得自体使用。我们的总体假设是 瘤内或静脉给药后，肿瘤靶向MC在体外和体内都能与癌细胞结合 并具有显著的抗肿瘤活性。在这里，我们将测定人MC的体外和体内活性 对抗几种癌症类型。这些研究可能导致针对不同癌症的新的采用细胞疗法 从淋巴瘤到乳腺癌。

ABSTRACT The role of human tissue mast cells (MC) in the pathology of many cancers is not known. Correlative studies in humans have found high MC numbers in the tumor microenvironment have pro- and anti-tumor effects and contrasting patient outcomes depending on the cancer types. We discovered that human MC, are activated by, and promote killing of, cancer cells in vitro and in vivo, infiltrate solid cell tumor masses, bind to tumors in vivo, can be obtained in quantities necessary for patient infusion, cryopreserved without loss of function, and display no overt toxic effects when injected intravenously into mice with engrafted human tumors. To develop this novel, cell-based cancer immunotherapy we will utilize FDA approved humanized IgE (which bind MC FcεRI with extremely high affinity) to target MC to cancer cells. This new approach is premised on efficient, autologous production of MC, tumor targeting, and effective tumor specific killing. This strategy has not been feasible heretofore as these cells reside in tissue and cannot be obtained for autologous use. Our overall hypothesis is tumor targeted MC will bind to cancer cells in vitro and in vivo after intratumoral or intravenous administration and elicit significant anti-tumor activity. Here we will determine the in vitro and in vivo activity of human MC against several cancer types. These studies could lead to new adoptive cell therapies for diverse cancers ranging from lymphoma to breast cancer.