Immunoregulation and immunotherapy of breast cancer

描述（由申请人提供）：为了激活乳腺癌患者的抗肿瘤T淋巴细胞应答，该提案靶向端粒酶逆转录酶hTERT作为几乎通用的肿瘤抗原，与抗CD 25 mAb daclizumab组合以抑制CD 4 + CD 25+阴性调节性T细胞。>95%的乳腺癌过表达hTERT（尽管在大多数正常细胞中沉默），hTERT+肿瘤细胞的存活需要功能活性的端粒酶。细胞毒性T淋巴细胞（CTL）识别来自hTERT的肽并杀死多种组织学的hTERT+肿瘤细胞。用hTERT肽接种癌症患者安全地诱导血液和肿瘤中的hTERT特异性CTL，在一些患者中与显著的肿瘤坏死相关。然而，CD 4 + CD 25+调节性T细胞主要存在于乳腺癌中，并抑制免疫应答，包括疫苗接种诱导的抗肿瘤T细胞应答。该提议的中心假设是，hTERT特异性疫苗接种与daclizumab组合以抑制体内调节性T细胞将放大抗肿瘤免疫应答，以在晚期乳腺癌患者中实现临床显著应答。为了检验这一假设，提出了用达克珠单抗施用hTERT肽疫苗接种的两项临床试验。在AIM ONE中，HLA-A2+患者将接受达克珠单抗，然后用三种hTERT肽与GM-CSF佐剂接种。其中一种肽靶向高亲和力hTERT CTL表位，两种异型肽靶向衍生自hTERT的新的低亲和力（“隐蔽”）CTL表位。该试验测试了该方法的安全性和免疫原性，并确定了daclizumab的最佳剂量，以最大限度地特异性破坏Treg频率和功能。在AIM TWO中，患者将在II期研究中随机接受单独的hTERT肽疫苗或疫苗加达克珠单抗。该试验将确定daclizumab对Treg功能破坏的影响，以及daclizumab对疫苗免疫原性和乳腺癌患者临床应答的影响。

DESCRIPTION (provided by applicant): To activate anti-tumor T lymphocyte responses in patients with breast cancer, this proposal targets the telomerase reverse transcriptase hTERT as a nearly universal tumor antigen in combination with the anti- CD25 mAb daclizumab to inhibit CD4+CD25+ negative regulatory T cells. hTERT is overexpressed by >95% of all breast carcinomas (although silent in most normal cells), and survival of hTERT+ tumor cells requires functionally active telomerase. Cytotoxic T lymphocytes (CTL) recognize peptides derived from hTERT and kill hTERT+ tumors cells of multiple histologies. Vaccination of cancer patients with hTERT peptide safely induces hTERT-specific CTL in blood and in tumor, associated in some patients with marked tumor necrosis. However, CD4+CD25+ regulatory T cells are found prominently in breast cancer and dampen immune responses, including anti-tumor T cell responses induced by vaccination. It is the central hypothesis of this proposal that hTERT-specific vaccination in combination with daclizumab to inhibit regulatory T cells in vivo will amplify anti-tumor immune responses to achieve clinically significant responses in patients with advanced breast cancer. To test this hypothesis, two clinical trials of hTERT peptide vaccination administered with daclizumab are proposed. In AIM ONE, HLA-A2+ patients will receive daclizumab followed by vaccination with three hTERT peptides in adjuvant with GM-CSF. One of the peptides targets a high affinity hTERT CTL epitope and two heteroclitic peptides target novel low-affinity ("cryptic") CTL epitopes derived from hTERT. This trial tests the safety and immunogenicity of the approach and determines the optimal dose of daclizumab to maximally and specifically disrupt Treg frequency and function. In AIM TWO, patients will be randomized in a phase II study to receive hTERT peptide vaccine alone or vaccine plus daclizumab. This trial will determine the effect of daclizumab on the disruption of Treg function and the effect of daclizumab on the immunogenicity of vaccine as well as clinical response of patients with breast cancer.