Immunotherapy of Cutaneous T-Cell Lymphoma with Interleukin-12

Interleukin-12 皮肤 T 细胞淋巴瘤的免疫治疗

• 批准号: 7679455
• 负责人: ALAIN H ROOK
• 金额: --
• 依托单位: WISTAR 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/7679455
• 关键词: Accounting; Apoptosis; CD4 Positive T Lymphocytes; Cells; Clinical Trials; Cutaneous; Cytotoxic T-Lymphocytes; Defect; Disease; Disease regression; Dose; Evaluable Disease; Helper-Inducer T-Lymphocyte; Immune; Immunologics; Immunotherapy; In Situ; Interferon Type II; Interleukin-12; Interleukin-2; Invasive; Lead; Lesion; Lymphocyte; Malignant Neoplasms; Multicenter Trials; Natural Killer Cells; Pathway interactions; Patients; Peripheral Blood Involvement; Phase I Clinical Trials; Phenotype; Play; Production; Recombinants; Refractory; Role; Signal Transduction; Skin; T-Cell Lymphoma; T-Lymphocyte; Work; clinical effect; cytokine; depressed cell-mediated immunity; in vivo; interleukin-12 receptor; outcome forecast; receptor; receptor expression; response; tumor

Cutaneous T-cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ T-lymphocytes with the phenotype of mature helper T-cells. Patients with advanced forms of CTCL characterized by rnultiple tumors or peripheral blood involvement typically have a poor prognosis. Our previous work has demonstrated that advanced CTCL is characterized by prominent immunologic defects including depressed cell-mediated immunity. A marked defect in IL-12 production in CTCL has also been noted, which may play a role in depressed cell-mediated immunity. Because evidence exists for an antitumor T-cell response and since IL-12 is pivotal in stimulating cytotoxic T-cells, several clinical trials have been performed with recombinant IL- 12 with 10 of 23 evaluable patients responding. Key observations in these small studies were 1) responses were rapid but were often eventually associated with an IL-12 refractory state, 2) the latter may be associated with downmodulation of IL-12 receptors on lymphocytes, 3) regressing lesions were intensely infiltrated with cytotoxic T-cells, and 4) more robust responses appeared to occur at the lower dose of 100 ng/kg used in the phase I trial. This proposal plans to study the in vivo effects of IL-12 in a newly initiated multicenter trial which will combine IL- 12 with escalating doses of IL-2. We propose to investigate the in vivo mechanisms of action of IL-12 by studying 1) skin infiltrating immune cells, 2) cytokine production in situ in skin lesions, and 3) extent of apoptosis within active skin lesions prior to and during IL-12 therapy and correlate this with lesion regression. We will also examine IL-12 responsive NK cell activity and interferon gamma production in concert with IL- 12 receptor expression and IL- 12 signal transduction prior to and prospectively during therapy to determine if downmodulation of receptors or alteration of Jak-Stat pathways accounts for tolerance to the clinical effects of IL-12. A more precise understanding of the effects of IL-12 will lead to the optimal use of this cytokine for this IL-12 responsive disease.

皮肤T细胞淋巴瘤（CTCL）是一种具有成熟辅助辅助辅助辅助T细胞的表型的CD4+ T淋巴细胞的克隆衍生的皮肤侵入性恶性肿瘤。具有肿瘤或周围血液参与的特征的晚期CTCL的患者通常预后较差。我们以前的工作表明，高级CTCL的特征是明显的免疫缺陷，包括抑郁症细胞介导的免疫。还指出了CTCL中IL-12产生的明显缺陷，这可能在抑郁细胞介导的免疫力中起作用。由于存在抗肿瘤T细胞反应的证据，并且由于IL-12在刺激细胞毒性T细胞中是关键的，因此对重组IL-12进行了几项临床试验，有23名可评估的患者中有10名临床试验。这些小型研究中的主要观察结果是1）反应很快，但最终通常与IL-12耐火态相关，2）后者可能与淋巴细胞上IL-12受体的下调相关，3）3）在胞毒性T-cell中的抑制作用降低，并在4）较低的时期浸润，并在4）较低的时期浸润。 审判。该提案计划在一项新启动的多中心试验中研究IL-12的体内影响，该试验将IL-12与IL-2的不断升级剂量相结合。我们建议通过研究1）皮肤浸润的免疫细胞来研究IL-12的体内作用机制，2）在皮肤病变中原位的细胞因子产生，以及3）IL-12治疗前和期间活性皮肤病变内凋亡的程度，并与这种病变回归相关。我们还将在与IL-12受体表达和IL-12信号的协同时一起检查IL-12响应式NK细胞活性和干扰素伽马的产生 在治疗期间和前瞻性转导，以确定受体的下调或JAK-STAT途径的改变是对IL-12的临床作用的耐受性。对IL-12的影响的更精确的理解将导致该细胞因子对这种IL-12反应性疾病的最佳使用。