Rebuilding T cells for Cancer Immunodeficiencies

 描述（由申请人提供）：根据美国癌症协会，每年约有170万美国人被诊断患有癌症。如果早期诊断，使用化疗、放疗和/或手术的标准治疗，大多数癌症的生存预后可能相对积极。在使用化疗和放疗的标准治疗期间，癌症患者经历淋巴细胞（B、T和NK细胞）的大量破坏。这种淋巴细胞减少症是一种诱导的继发性免疫缺陷，破坏了大量的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对抗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治疗剂，在淋巴细胞减少症患者的恢复过程中迅速将T细胞群恢复到正常健康水平。这些新的蛋白质生物制剂将激活促生存白细胞介素-7（IL-7）信号通路，该通路在T细胞的发育、分化、增殖和稳态中至关重要。我的实验室已经在原子分辨率上破译了IL-7信号传导的分子机制，现在正准备将我们的结果转化为有益的治疗方法。 人类健康和疾病的战略。我们假设存在比天然野生型IL-7蛋白序列功能更好的IL-7蛋白序列，并且可能能够调节特异性T细胞群。我们将通过利用我们实验室中开发的新技术开发这些新的“超级IL-7”激动剂，所述新技术使用噬菌体展示诱变，这将使我们能够以高通量组合方法优化对其受体的结合亲和力和信号输出。我们将以高蛋白产量生产这些新的超级IL-7激动剂，并使用结构，生物物理和细胞化学方法表征其功能特性。 基于这些方法，包括圆二色性、表面等离子体共振、量热法、流式细胞术以及细胞存活和增殖测定。这些蛋白质的一个子集的初步研究 生物制剂将在标准鼠模型中进行以测试体内效应。两年资助期结束时的目标将是通过额外的资金资源确定适合在小鼠模型中进行进一步临床前测试的超级IL-7激动剂。这些新的IL-7激动剂也可以应用于其他状态的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离体T细胞增强剂，并作为新的免疫试剂，以进一步描绘IL-7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.