Clinical Development of anti-OX40 and OX40L

描述（由申请人提供）：免疫疗法在治疗乳腺癌、黑色素瘤、肾细胞癌和非霍奇金淋巴瘤等多种癌症方面显示出巨大的潜力；然而，尽管有新的抗原特异性疫苗、细胞疗法、抗体和细胞因子，免疫疗法的全部潜力尚未实现。癌症免疫治疗应答率低的原因有很多，但最根本的问题之一是癌症患者出现以t细胞效应和记忆功能下降为特征的进行性免疫抑制。安德鲁·温伯格（Andrew Weinberg）博士实验室的实验描述了一种存在于T细胞上的免疫调节分子OX40。与本研究相关的OX40参与的结果包括记忆T细胞的产生，效应T细胞向外周的迁移增加，效应T细胞产生的细胞因子增加，以及在体内破坏外周T细胞耐受性的能力。OX40+ T细胞广泛存在于各种人类肿瘤和肿瘤累及的淋巴结中。基于ox40的治疗在多种动物肿瘤模型中引起肿瘤消退，并且在小鼠和非人灵长类动物临床前实验中耐受性良好。这项研究将首次研究基于ox40的人类癌症治疗方法。拟议研究的具体目的是通过进行I期临床试验来确定抗ox40耐受良好的剂量，用于未来的人体临床试验，利用已建立的免疫监测技术（如ELISA和细胞因子流式细胞术）描述抗ox40治疗后对报告抗原的初级和回忆免疫反应。以及生产含有受体结合结构域且匹配或超过OX40激动剂抗体的生物活性的人OX40配体的可溶形式。

DESCRIPTION (provided by applicant): Immunotherapy has shown great potential in the treatment of a variety of cancers such as breast cancer, melanoma, renal cell carcinoma and non-Hodgkin's lymphoma; however, the full potential of immunotherapy has not been achieved despite new antigen-specific vaccines, cellular therapy, antibodies, and cytokines. The reasons for the low response rate in cancer immunotherapy are many, but one of the most fundamental issues is that cancer patients develop progressive immunosuppression characterized by decreased T-cell effector and memory function. Experiments in the laboratory of Dr. Andrew Weinberg have described an immunological regulatory molecule present on T cells called OX40. The consequences of OX40 engagement relevant to the proposed research include generation of memory T cells, increased migration of effector T cells into the periphery, enhanced cytokine production by effector T cells, and the ability to break peripheral T-cell tolerance in vivo. OX40+ T cells are present in a wide variety of human tumors and in tumor-involved lymph nodes. OX40-based therapy causes tumor regression in a variety of animal tumor models, and was well-tolerated in murine and non-human primate pre-clinical experiments. This research will be the first to study OX40-based cancer therapy in humans. The specific aims of the proposed research are to define a well-tolerated dose of anti-OX40 for use in future clinical trials in humans by performing a phase I clinical trial, characterize the primary and recall immune responses to reporter antigens after anti-OX40 treatment using established immunological monitoring techniques such as ELISA and cytokine flow cytometry, and to produce a soluble form of the human OX40 ligand that contains the receptor-binding domain and matches or exceeds the biologic activity of the OX40 agonist antibody.