Rebuilding T cells for Cancer Immunodeficiencies

 描述(申请人提供)：根据美国癌症协会的数据，每年约有170万美国人被诊断出患有癌症。如果及早诊断，对于大多数使用标准化疗、放射治疗和/或手术治疗的癌症来说，生存预后可能是相对积极的。在使用化疗和放射治疗的标准治疗期间，癌症患者会经历淋巴细胞(B、T和NK细胞)的大量破坏。这种淋巴细胞减少症是一种诱发的继发性免疫缺陷，会破坏大量的T细胞。如果没有正常的健康T细胞水平，适应性免疫反应将无法正常发挥作用，以对抗新发展的肿瘤或进一步的机会性感染。在这项提案中，我们的目标是开发下一代蛋白质疗法，在淋巴细胞减少症患者康复期间，将T细胞数量迅速恢复到正常健康水平。这些新的蛋白质生物制剂将激活生存的白介素7(IL-7)信号通路，该信号通路在T细胞的发育、分化、增殖和动态平衡中至关重要。我的实验室已经破译了原子分辨率下IL-7信号的分子机制，现在准备将我们的结果转化为有益的治疗 人类健康和疾病战略。我们假设，有一些IL-7蛋白序列将比天然的野生型IL-7蛋白序列功能更好，并可能能够调节特定的T细胞群。我们将利用我们实验室开发的利用噬菌体展示突变的新技术来开发这些新的超级IL-7激动剂，这将使我们能够以高通量组合的方法优化与其受体的结合亲和力和信号输出。我们将以高蛋白产量产生这些新的超级IL-7激动剂，并利用结构、生物物理和细胞来表征它们的功能特性 基于圆二色谱、表面等离子共振、量热法、流式细胞术以及细胞存活和增殖分析的方法。这些蛋白质的一个子集的初步研究 生物制剂将在标准的小鼠模型中进行，以测试体内效应。在为期两年的资助期结束时，目标将是通过额外的资金来源，确定适合于进一步在小鼠模型中进行临床前试验的超级IL-7激动剂。这些新的IL-7激动剂也可能用于其他状态的T细胞淋巴细胞减少症，包括败血症和HIV感染，作为新的疫苗佐剂，作为过继免疫治疗的体外T细胞增强剂，以及作为新的免疫学试剂来进一步描述IL-7的免疫生物学。

 DESCRIPTION (provided by applicant): Approximately 1.7 million Americans are diagnosed annually with cancer according to the American Cancer Society. If diagnosed early, the prognosis of survival may be relatively positive for the majority of cancers using standard treatments of chemotherapy, radiation, and/or surgery. During standard treatment using chemotherapy and radiation, cancer patients experience a large destruction of lymphocytes (B, T, and NK cells). This lymphopenia, which is a type of induced secondary immunodeficiency, destroys large numbers of T cells. Without normal healthy T cell levels, the adaptive immune response will not function properly to battle newly developing neoplasias or combat further opportunistic infections. In this proposal, we aim to develop next generation protein therapeutics that will restore T cell populations to normal healthy levels quickly during the recovery of patients with lymphopenia. These new protein biologics will activate the prosurvival interleukin-7 (IL-7) signaling pathway that is essential in the development, differentiation, proliferation, and homeostasis of T cells. My laboratory has deciphered the molecular mechanisms of IL-7 signaling at atomic resolution and is now poised to translate our results into beneficial treatment strategies for human health and diseases. We hypothesize that there are IL-7 protein sequences that will function better than the native wild- type IL-7 protein sequence and possibly be able to tune specific T cell populations. We will develop these new `super IL-7' agonists by capitalizing on new technology developed in our laboratory using phage display mutagenesis that will enable us to optimize binding affinity and signaling output to its receptors in a high- throughput combinatorial approach. We will generate these new super IL-7 agonists in high protein yields and characterize their functional properties using structural, biophysical, and cell based approaches including circular dichroism, surface plasmon resonance, calorimetry, flow cytometry, and cell survival and proliferation assays. Initial studies of a subset of these protein biologics will be conducted in standard murine models to test in vivo effects. The goal at the end of the two-year funding period will be to identify super IL-7 agonists suitable for further preclinical testing in murine models through additional funding resources. These new IL-7 agonists may also find application in other states of T cell lymphopenia including sepsis and HIV infections, as new vaccince adjuvants, as ex vivo T cell enhancers for adoptive immunotherapy, and as novel immunological reagents to further delineate IL-7 immunobiology.