TCR Targeting Antibodies for the Treatment of T cell Cancers

项目摘要 抗体介导的靶向免疫疗法在杀死癌细胞方面非常有效。T细胞白血病 淋巴瘤，统称为T细胞癌，每年影响全球约10万名患者。旧病复发 T细胞癌对激进的化疗反应很差，5年生存率在7%到38%之间。因此，T 细胞癌尤其需要抗体介导的靶向免疫治疗来改善患者的预后。 然而，开发针对T细胞癌的免疫疗法是具有挑战性的，因为免疫疗法将不得不 保存足够多的健康T细胞，以维持正常运行的免疫系统。T细胞表达T细胞受体 (TCR)在细胞表面。尽管所有T细胞都表达TCR，但可以根据TCRβ来区分它们 链恒定区(TRBC)，源于两个基因片段中的一个，TRBC1或TRBC2。我带领了一支队伍 这表明在健康的T细胞群体中，大约45%的细胞表达TRBC1，而另外55%的细胞表达TRBC1 特快TRBC2。然而，克隆性T细胞癌表达TRBC1或TRBC2(Paul等人，科学。事务处理地中海医院。 2021年)。因此，我假设抗体介导的特异性TRBC1或TRBC2靶向将根除克隆 T细胞癌，同时保留了一半健康的多克隆T细胞。我还开发了一款TRBC1- 靶向双特异性抗体(αTRBC_1)选择性杀伤TRBC_1~+T细胞癌(和TRBC_1~+健康T细胞) 同时体外保存健康的TRBC2+T细胞。这些体外观察将需要在 在启动未来的人类临床试验之前建立动物模型。对于目标1，我将确定在体内的活性 αTRBC1二功能抗体。我将测试αTRBc1抗体在多发性硬化患者中诱导肿瘤消退的能力 T细胞癌的小鼠模型。然后我将检查剩余的健康TRBC2+T细胞是否保留了所有 免疫系统正常运行所需的免疫细胞亚群。我还会测试治疗压力是否来自 αTRBC1二功能抗体将导致低表达TCRT细胞群，该T细胞群将对 心理治疗。对于目标2，我将测试TRBC2靶向T细胞癌的可行性。作为靶向TRBC2的抗体 目前还无法获得，我将使用噬菌体展示来开发TRBC2特异性抗体。然后我会测试一下 TRBC2靶向抗体在体外和多种小鼠T细胞癌模型中的细胞毒性。我们的TRBC- 定向抗体将填补治疗T细胞癌患者的未得到满足的需求。建议的体内和 机械学研究将提供启动早期人类所需的临床前验证 将测试TRBC1和TRBC2靶向抗体的安全性和有效性的临床试验。 我的长期目标是成为一名独立的实验室医生兼科学家，专注于 开发T细胞癌的新治疗方法。通过这项提议，我还将获得 达到这一目标所需的研究技能和职业经验。这些技能将是发展的关键 在人类T细胞白血病和淋巴瘤方面的相关的、有影响力的翻译研究计划。

Project Summary Antibody-mediated targeted immunotherapies are highly effective in killing cancer cells. T cell leukemias and lymphomas, collectively known as T cell cancers, affect ~100,000 patients worldwide each year. Relapsed T cell cancers respond poorly to aggressive chemotherapy with a 5-year survival between 7% to 38%. Thus, T cell cancers particularly warrant antibody-mediated targeted immunotherapy to improve patient outcomes. However, developing a T cell cancer targeting immunotherapy is challenging as the immunotherapy will have to preserve enough healthy T cells to maintain a functioning immune system. T cells express the T cell receptor (TCR) on the cell-surface. Although all T cells express TCR, they can be distinguished based on the TCR beta chain constant region (TRBC) which is derived from one of two gene segments, TRBC1 or TRBC2. I led a team that demonstrated that in healthy T cell populations, about 45% of cells express TRBC1 while the other 55% express TRBC2. However, clonal T cell cancers express either TRBC1 or TRBC2 (Paul et al., Sci. Transl. Med. 2021). Thus, I hypothesize that antibody-mediated specific TRBC1 or TRBC2 targeting will eradicate the clonal T cell cancers while preserving half of the healthy polyclonal T cell population. I also developed a TRBC1- targeting bispecific antibody (αTRBC1) that selectively kills TRBC1+ T cell cancers (and TRBC1+ healthy T cells) while preserving the healthy TRBC2+ T cells in vitro. These in vitro observations will require confirmation in animal models before initiation of future human clinical trials. For Aim 1, I will determine the in vivo activity of the αTRBC1 bispecific antibody. I will test the ability of αTRBC1 antibodies to induce tumor regression in multiple mouse models of T cell cancers. I will then examine if the remaining healthy TRBC2+ T cells retain all of the immune cell subsets required for a functioning immune system. I will also test if therapeutic pressure from the αTRBC1 bispecific antibody will give rise to a low TCR expressing T cell population that will be resistant to therapy. For Aim 2, I will test feasibility of TRBC2-targeting on T cell cancers. As a TRBC2-targeting antibody is currently unavailable, I will use phage display to develop TRBC2-specific antibodies. I will then test the cytotoxicity of TRBC2 targeting antibodies in vitro and in multiple mouse models of T cell cancers. Our TRBC- directed antibodies will fill an unmet need for the treatment of T cell cancer patients. The proposed in vivo and mechanistic studies will provide the pre-clinical validation required for the initiation of an early-phase human clinical trials that will test the safety and efficacy of TRBC1- and TRBC2-targeting antibodies. My long-term goal is to become an independent laboratory-based physician-scientist focusing on developing novel therapeutic approaches for T cell cancers. Through this proposal, I will also acquire the research skills and career experience needed to reach this goal. These skills will be critical to the development of a relevant, impactful translational research program in human T cell leukemias and lymphomas.