Immunoregulation and immunotherapy of breast cancer

描述(由申请人提供)：肿瘤生长和发展所必需的分子是癌症新免疫疗法的有希望的靶点，然而宿主免疫抑制因素对将这一假说转化为临床成功构成重大挑战。这项建议通过将针对人类端粒酶逆转录酶(HTERT)和Survivin的新型疫苗与抗CD25抗体Daclizumab结合在激素受体阳性(HR+)转移疾病患者中来解决乳腺癌中的这些障碍。HTERT和Survivin在90%的人类乳腺肿瘤中表达，但在正常细胞中很少表达，每一种都是恶性表型的关键因素。我们已经证明，细胞毒性T淋巴细胞识别来自hTERT和Survivin的多肽，并在广泛的组织学中杀伤表达这些蛋白的肿瘤细胞。在之前的资助期间，我们给转移性乳腺癌患者接种了单一的hTERT多肽，并展示了血液和肿瘤中hTERT特异性CD8+T细胞的诱导，与肿瘤微环境的重大变化和总体生存率的增加有关。我们还发现，免疫抑制调节性T细胞(Tregs)在乳腺癌中含量丰富，在一项初步的临床研究中，单次注射抗CD25单抗(MAb)Daclizumab会导致患者体内CD4+Foxp3+CD25+Tregs的耗竭时间达到以前无法达到的水平。我们推测，hTERT和Survivin疫苗联合Daclizumab去除调节性T细胞可以诱导抗肿瘤免疫反应，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，使用已被FDA批准进行研究的第二代疫苗，并在佐剂GM-CSF中涉及多个hTERT和Survivin多肽，以及含有CRM197的肺炎球菌疫苗Prevnar(PCV)，后者是一种诱导T细胞帮助的新方法。在第一个目标中，通过首次或随后的激素治疗进展为HR+转移性乳腺癌的人类白细胞抗原-A2+患者将随机接受下一步适当的激素治疗和使用或不使用Daclizumab的hTERT/Survivin/PCV疫苗接种，以评估Treg耗尽对疫苗免疫原性的影响。在第二个目标中，对于HR+的转移性疾病并通过第一次激素治疗进展的HLAA2+患者，将接受二线激素治疗，包括疫苗或不使用疫苗。因此，从目标一到目标二，代表着我们的方法顺利和合理地扩展到更大的健康和较少接受严重预治疗的HR+转移性疾病患者队列。在这两个目标中，将对T细胞反应和Treg调节进行免疫学监测，以提供与观察到的临床效果相关的免疫机制的见解。其目标是建立一种免疫强效疫苗，为HR+转移性乳腺癌患者提供临床益处。公共卫生相关性：我们的目标是确定针对hTERT和Survivin的新型疫苗在转移性激素受体阳性乳腺癌患者中使用和不使用Daclizumab的免疫学和临床影响。建议的临床试验中的所有患者还将按照护理标准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治疗方法，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.