Conditioning Patients to Increase DC-vaccine Potency

对患者进行调理以提高 DC 疫苗的效力

• 批准号: 7460927
• 负责人: JOSEPH Wayne FAY
• 金额: $ 19.67万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7460927
• 关键词: Address; Aliquot; Antigens; Biological Assay; Blood; Blood specimen; CD34 gene; CD4 Positive T Lymphocytes; CD8 Antigens; CD8B1 gene; CXCR3 gene; Cells; Clinical; Clinical Trials; Clinical effectiveness; Cyclophosphamide; Dendritic Cell Vaccine; Dendritic Cells; Disease Progression; Failure; Flow Cytometry; Flu matrix protein; HIV; Hematopoietic; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunotherapy; Influenza; Integration Host Factors; Interferon Type II; Interleukin-10; Keyhole Limpet Hemocyanin; Lymphocyte; Measures; Metastatic Melanoma; Monitor; Outcome; Patients; Peptides; Phase; Phenotype; Physiologic pulse; Placebos; Principal Investigator; Production; Progressive Disease; Pulse taking; Randomized Clinical Trials; Rate; Regulation; Research; Staging; Stem cells; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tumor Antigens; Vaccination; Vaccine Antigen; Vaccines; conditioning; flu; immunogenicity; improved; in vivo; melanoma; programs; research study; response; tumor

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).

使用源自 CD34+ 的树突状细胞 (DC) 对患有转移性黑色素瘤的 HLA-A*201 患者进行疫苗接种 载有黑色素瘤肽抗原、KLH 和流感的造血细胞祖细胞 (CD34+HPC) 肽可诱导 CD8+ T 细胞对黑色素瘤肽的免疫，并具有一些临床益处。 通过在黑色素瘤肽存在的情况下产生干扰素-γ来测量免疫力 通过从血液中获得的 CD8+ T 细胞控制抗原。 T 细胞免疫与早期临床结果相关 和生存。早期进展的患者要么没有 T 细胞免疫，要么对 DC 具有短暂的 T 细胞免疫 疫苗接种。这些细胞中缺乏 DC 诱导的 CD8+ T 细胞免疫可能有多种原因。 患者的情况包括：DC 无法启动 T 细胞对抗肿瘤抗原、肿瘤的存在 由宿主抑制性淋巴细胞诱导的特异性耐受性和抗黑色素瘤 T 细胞不足 剧目。 AIM 1 将确定 IV 期黑色素瘤患者是否接受 CPA 预处理 改善 DC 疫苗接种后的免疫和临床反应。我们将进行 l/ll 阶段随机化 随后接受安慰剂或 CPA (500mg/m2) 治疗的 IV 期黑色素瘤患者的临床试验 通过用黑色素瘤肽和 KLH 脉冲的 CD34-DC 进行疫苗接种。作为对照，单独等分 DC 将用 HIV 肽作为新抗原进行脉冲，该新抗原将与负载肽的 DC 混合并 同时给予。主要结果是诱导黑色素瘤特异性 CD8+T 细胞 免疫。次要结果是客观临床反应率。第三级成果是： 调节性/抑制性 CD4+T 细胞 (AIM 2) 的减少和 HIV 特异性 CD8+T 细胞的启动 (AIM 3)。