Project 3

摘要 以疫苗为基础的乳腺癌预防是一项很有前途的战略，可大大减少 疾病的发病率、治疗和死亡率，因为疫苗可以诱导高度特异性的免疫反应， 在没有疾病的情况下自我调节。靶向乳腺癌表达抗原的疫苗正在进行的临床试验 癌细胞，包括该研究小组成员正在进行的试验，已经表明疫苗可以诱导 基于T细胞的免疫力可以持续数年。有效实施预防疫苗将需要 确定哪些抗原与乳腺癌风险和进展相关，并确定组织- 和基于血液的疫苗反应指标。在这个项目中提出的实验将与我们的新的 一种新型多抗原预防疫苗的Ib期试验，以推进其临床预防试验。在我们 第一个具体目标，我们将利用广泛的组织资源，妇女诊断为良性乳腺癌 在马约诊所和卡马诺斯癌症中心对疾病进行评估，以评估哪种抗原可以预防 疫苗在癌前乳腺组织中表达，并且与随后的乳腺癌最相关。 癌症发展该信息对于鉴定哪些抗原应被包括在本发明的组合物中是至关重要的。 未来的预防试验，哪些患者最有可能从中受益。在我们的第二个具体目标，我们将 评估本阶段对多抗原疫苗的血液抗体和细胞免疫应答 1B临床试验。我们将使用高维细胞分析和靶向测序方法， 这将为未来更大规模的预防试验提供免疫应答的微创终点。在 我们的第三个具体目标，我们将评估疫苗接种前和接种后的正常乳腺组织背景， 确定抗原表达的变化如何与特异性免疫激活相关的临床试验 细胞亚型以及T和B细胞库的变化。这些信息将为未来的预防试验提供信息 通过定义疫苗及其特定组分如何影响抗原表达和免疫应答， 非恶性乳腺组织该项目的成功完成将确定哪些疫苗成分应 推进到一个更大的基于疫苗的乳腺癌预防临床试验，这有可能推动 总体疾病发病率、负担和死亡率显著降低。

ABSTRACT Vaccine-based prevention of breast cancer is a promising strategy for substantially reducing the impact of disease incidence, treatment, and mortality because vaccines can induce highly specific immune responses that self-regulate in the absence of disease. Ongoing clinical trials of vaccines targeting antigens expressed by breast cancer cells, including ongoing trials from members of this research group, have shown that vaccines can induce T-cell-based immunity that can last for years. Effective implementation of a prevention vaccine will require identification of which antigens are associated with breast cancer risk and progression and definition of tissue- and blood-based metrics of vaccine response. The experiments presented in this project will pair with our new Phase Ib trial of a novel multi-antigen prevention vaccine to advance it toward a clinical prevention trial. In our first Specific Aim, we will draw upon an extensive tissue resource of women diagnosed with benign breast disease at the Mayo Clinic and at the Karmanos Cancer Center to assess which of the antigens in the prevention vaccine are expressed in premalignant breast tissue and which are most associated with subsequent breast cancer development. This information will be critical for identifying which antigens should be included in the future prevention trial and which patients are most likely to benefit from it. In our second Specific Aim, we will evaluate blood-based antibody and cellular immune responses to the multiantigen vaccine in our current Phase 1b clinical trial. We will use high dimensional cellular analysis and targeted sequencing approaches, information that will provide minimally invasive endpoints of immune response for a larger scale future prevention trial. In our third Specific Aim, we will assess pre- and post-vaccine background normal breast tissues from patients in the clinical trial to identify how changes in antigen expression are associated with activation of specific immune cell subtypes and changes in the T- and B-cell repertoire. This information will inform the future prevention trial by defining how the vaccine and its specific components impact antigen expression and immune response in nonmalignant breast tissue. Successful completion of this project will define which vaccine components should be advanced to a larger vaccine-based breast cancer prevention clinical trial, which has the potential to drive significant reductions in overall disease incidence, burden and mortality.