Clinical Development of anti-OX40 and OX40L

描述(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，免疫疗法的潜力还没有完全实现。癌症免疫治疗应答率低的原因是多方面的，但最根本的原因之一是癌症患者出现进行性免疫抑制，其特征是T细胞效应器和记忆功能降低。安德鲁·温伯格博士实验室的实验描述了T细胞上存在的一种名为OX40的免疫调节分子。与拟议的研究相关的OX40参与的结果包括产生记忆T细胞，增加效应T细胞向外周的迁移，增强效应T细胞产生细胞因子的能力，以及在体内打破外周T细胞耐受的能力。OX40+T细胞广泛存在于多种人类肿瘤和肿瘤累及的淋巴结中。基于OX40的治疗在各种动物肿瘤模型中导致肿瘤消退，并且在小鼠和非人类灵长类临床前实验中耐受性良好。这项研究将是第一次研究基于OX40的人类癌症疗法。这项拟议研究的具体目的是通过执行I期临床试验，确定用于未来临床试验的良好耐受量的抗OX40，利用已建立的免疫监测技术，如ELISA和细胞因子流式细胞术，表征抗OX40治疗后对报告抗原的初级和召回免疫反应，并生产一种含有受体结合结构域并与OX40激动剂抗体的生物学活性相匹配或超过的人OX40配体的可溶性形式。

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.