Immunoregulation and immunotherapy of breast cancer

描述（由申请人提供）：肿瘤生长和发育所必需的分子代表了新型癌症免疫治疗的有希望的靶点，但宿主免疫抑制因子对将该假设转化为临床成功提出了重大挑战。该提案通过将针对人端粒酶逆转录酶（hTERT）和存活素的新型疫苗与抗CD 25抗体daclizumab组合用于激素受体阳性（HR+）转移性疾病患者来解决乳腺癌中的这些障碍。hTERT和生存素在>90%的人乳腺肿瘤中表达，但很少在正常细胞中表达，并且每种都对恶性表型有重要贡献。我们已经表明，细胞毒性T淋巴细胞识别来自hTERT和生存素的肽，并杀死表达这些蛋白质的肿瘤细胞在广泛的组织学。在之前的资助期间，我们用单一hTERT肽接种转移性乳腺癌患者，并证明了血液和肿瘤中hTERT特异性CD 8 + T细胞的诱导，与肿瘤微环境的重大改变和总生存期的增加相关。我们还发现，免疫抑制调节性T细胞（T细胞）在乳腺癌中是丰富的，在一项初步临床研究中，单次输注抗CD 25单克隆抗体（mAb）daclizumab导致患者中CD 4 + Foxp 3 + CD 25 + T细胞的长期消耗，达到以前无法达到的水平。我们假设针对hTERT和生存素的疫苗与daclizumab联合使用以耗尽调节性T细胞可以诱导抗肿瘤免疫应答，并为HR+转移性乳腺癌患者提供临床益处。为了验证这一假设，我们提出了两个随机临床试验，采用第二代疫苗已经批准FDA的调查，涉及多种hTERT和生存素肽的佐剂，GM-CSF，和CRM 197含有肺炎球菌疫苗Prevnar（PCV），后者是一种新的方法来诱导T细胞的帮助。在目标一中，通过转移性疾病的首次或后续激素疗法进展的患有HR+转移性乳腺癌的HLA-A2+患者将被随机化以接受下一个适当的激素疗法和有或没有达克珠单抗的hTERT/生存素/PCV疫苗接种，以评估Treg耗竭对疫苗免疫原性的影响。在目标二中，患有HR+转移性疾病并且通过转移性疾病的第一激素治疗进展的HLA-A2+患者将接受有或没有疫苗的二线激素治疗。因此，从目标一到目标二的转变代表了我们的方法顺利和合理地扩展到更大的健康和未经大量治疗的HR+转移性疾病患者队列。在这两个目标中，将进行T细胞应答和Treg调节的免疫学监测，以深入了解与观察到的临床效应相关的免疫机制。目标是建立一种免疫有效的疫苗，为HR+转移性乳腺癌患者提供临床获益。公共卫生相关性：我们的目的是确定一种靶向hTERT和生存素的新型疫苗在转移性激素受体阳性乳腺癌患者中的免疫学和临床影响。在拟议的临床试验中，所有患者也将按照标准治疗接受下一次适当的激素治疗。长期目标是开发一种基于免疫的疗法，为激素受体阳性乳腺癌患者提供临床益处。

DESCRIPTION (provided by applicant): Molecules essential for tumor growth and development represent promising targets for novel immunotherapy of cancer, yet host immunosuppressive factors impose major challenges for translating this hypothesis into clinical success. This proposal addresses these obstacles in breast cancer by combining a novel vaccine against the human telomerase reverse transcriptase (hTERT) and survivin in combination with anti-CD25 antibody daclizumab in patients with hormone receptor positive (HR+) metastatic disease. hTERT and survivin are expressed in >90% of human breast tumors but rarely in normal cells, and each critically contributes to the malignant phenotype. We have shown that cytotoxic T lymphocytes recognize peptides derived from hTERT and survivin and kill tumors cells expressing these proteins across a wide range of histologies. During the previous funding period, we vaccinated patients with metastatic breast cancer with a single hTERT peptide and demonstrated the induction of hTERT- specific CD8+ T cells in both blood and tumor, associated with major alterations in the tumor micro- environment and increased overall survival. We also found that immunosuppressive regulatory T cells (Tregs) are abundant in breast cancer and in a pilot clinical study, a single infusion of the anti-CD25 monoclonal antibody (mAb) daclizumab resulted in prolonged depletion of CD4+ Foxp3+ CD25+ Tregs in patients at a level not previously achievable. We hypothesize that a vaccine against hTERT and survivin in combination with daclizumab to deplete regulatory T cells can induce anti-tumor immune responses and offer clinical benefit for patients with HR+ metastatic breast cancer. To test this hypothesis, we propose two randomized clinical trials employing a second-generation vaccine already approved for investigation by FDA and involving multiple hTERT and survivin peptides in adjuvant, GM-CSF, and the CRM197-containing pneumococcal vaccine Prevnar (PCV), the latter a novel approach to induce T cell help. In Aim One, HLA-A2+ patients with HR+ metastatic breast cancer with progression through first or subsequent hormonal therapy for metastatic disease will be randomized to receive next appropriate hormonal therapy and hTERT/survivin/PCV vaccination with or without daclizumab to assess the effect of Treg depletion on the immunogenicity of the vaccine. In Aim Two, HLA-A2+ patients with HR+ metastatic disease and progression through first hormonal therapy for metastatic disease will receive second-line hormonal therapy with or without vaccine. The move from Aim One to Aim Two, therefore, represents a smooth and justified extension of our approach to a larger cohort of healthier and less heavily pretreated patients with HR+ metastatic disease. In both aims, immunological monitoring of T cell responses and Treg modulation will be performed to provide insights into immune mechanisms related to the observed clinical effects. The goal is to establish an immunologically potent vaccine that offers clinical benefit for patients with HR+ metastatic breast cancer. PUBLIC HEALTH RELEVANCE: We aim to determine the immunological and clinical impact of a novel vaccine targeting hTERT and survivin with and without daclizumab in patients with metastatic hormone receptor positive breast cancer. All patients in the proposed clinical trials will also receive the next appropriate hormone therapy per standard of care. The long-term goal is to develop an immune-based therapy that offers clinical benefit to patients with hormone receptor positive breast cancer.