Conditioning Patients to Increase DC-vaccine Potency

用来源于CD 34+的树突状细胞（DC）接种患有转移性黑素瘤的HLA-A*201患者 加载有黑素瘤肽抗原、KLH和流感病毒的造血细胞祖细胞（CD 34 + HPC） 肽导致对黑素瘤肽的CD 8 + T细胞免疫的诱导和一些临床益处。 免疫力通过在黑素瘤肽存在下干扰素-γ的产生来测量， 通过从血液中获得的CD 8 + T细胞控制抗原。T细胞免疫与早期临床结局相关 和生存早期进展的患者要么没有T细胞免疫，要么对DC有短暂的T细胞免疫 预防针在这些受试者中，DC诱导的CD 8 + T细胞免疫的缺乏可能有几个原因。 包括：DC不能针对肿瘤抗原引发T细胞，肿瘤细胞的存在， 宿主抑制性淋巴细胞诱导的特异性耐受和抗黑色素瘤T细胞不足 保留曲目。目的1将确定是否与CPA的IV期黑色素瘤患者的预治疗 改善DC疫苗接种后的免疫和临床应答。我们将进行I/II期随机 IV期黑色素瘤患者接受安慰剂或CPA（500 mg/m2）的临床试验， 通过用黑素瘤肽和KLH脉冲的CD 34-DC接种。作为对照，将单独等分的 DC将用作为新抗原的HIV肽脉冲，所述新抗原将与负载肽的DC混合， 同时管理。主要结果是黑色素瘤特异性CD 8 +T细胞的诱导 免疫力次要结局是客观临床应答率。三级结局为： 减少调节/抑制性CD 4 +T细胞（AIM 2）和引发HIV特异性CD 8 +T细胞（AIM 3）。

Vaccination of HLA-A*201 patients with metastatic melanoma with dendritic cells (DCs) derived from CD34+ hematopoietic cell progenitor cells (CD34+HPCs) loaded with melanoma peptide antigens, KLH and flu peptide resulted in the induction of CD8+ T cell immunity to melanoma peptides and some clinical benefit. Immunity was measured by the production of interferon-gamma in the presence of melanoma peptides and control antigens by CD8+ T cells obtained from blood. T cell immunity correlated with early clinical outcome and survival. Patients who progressed early had either no T cell immunity or transient T cell immunity to DC vaccination. There may be several reasons for the absence of DC-induced CD8+ T cell immunity in these patients including: the inability of DCs to prime T cells against tumor antigens, the presence of tumor specific tolerance induced by host suppressor lymphocytes, and an insufficient anti-melanoma T cell repertoire. AIM 1 will determine whether pre-treatment of patients with stage IV melanoma with CPA improves the immune and clinical response after DC vaccination. We will carry out a phase l/ll randomized clinical trial in patients with stage IV melanoma who will receive either placebo or CPA (500mg/m2) followed by vaccination with CD34-DCs pulsed with melanoma peptides and KLH. As a control, a separate aliquot of DCs will be pulsed with HIV peptides as neoantigens that will be mixed with the peptide-loaded DCs and administered at the same time. The primary outcome is the induction of melanoma-specific CD8+T cell immunity. The secondary outcome is the rate of objective clinical responses. Tertiary outcomes are: reduction of regulatory/suppressor CD4+T cells (AIM 2) and priming of HIV-specific CD8+T cells (AIM 3).