Immunotherapy by CD40 stimulation and IL-2 against Cancer

通过 CD40 刺激和 IL-2 对抗癌症的免疫疗法

• 批准号: 8653250
• 负责人: WILLIAM JOSEPH MURPHY
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653250
• 关键词: Advanced Malignant Neoplasm; Affect; Agonist; Antibodies; Apoptotic; B-Cell Lymphomas; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Carcinoma; Cell Count; Cell Death; Cell physiology; Cells; Cessation of life; Clinical; Combined Modality Therapy; Complex; Data; Dendritic Cells; Disadvantaged; Disease; Dominant-Negative Mutation; Dose; Excision; Funding; Generations; Goals; Grant; IL2 gene; Immune; Immune response; Immunotherapy; Implant; In Vitro; Indolent; Inflammatory; Interferon Type II; Interleukin-2; Kidney; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Renal Cell Cancer; Modeling; Molecular; Mus; Natural Immunity; Nature; Neoplasm Metastasis; Patients; Population; Predisposition; Primary Neoplasm; Reagent; Regulation; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Role; Signal Transduction; Solid Neoplasm; Streptozocin; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Time; Toll-like receptors; Tumor Antigens; Tumor Biology; Whole-Body Irradiation; adaptive immunity; cancer therapy; chemokine; combat; cytokine; gene induction; insight; killings; memory CD4 T lymphocyte; neoplastic cell; prevent; receptor expression; response; tumor

Treatment options for patients with advanced cancer are seriously limited. Selective immune attack provides a means to combat disseminated disease. CD40-CD40L interactions have been demonstrated to be critical in the generation of optimal immune responses. We have recently demonstrated that CD40 stimulation using an agonist antibody combined with IL2 can result in highly synergistic anti-tumor responses in mice bearing advanced metastatic renal cell carcinomas (RCC) and other solid tumors. Significant protection occurred using the combination only. This protection was correlated with significant increases in dendritic cell and tumor-specific CD8+ T cell numbers and surprisingly, independent of CD4+ T cell responses. We now propose to delineate the mechanisms underlying these synergistic anti-tumor responses and optimize them. Toward this goal we have developed three specific aims. Specific Aim 1 will determine the effects of CD40 stimulation on the tumor itself. While CD40 stimulation has been shown to induce activation-induced cell death (AICD) on a variety of B cell lymphomas, the effect on solid tumors is controversial and much less clear. Preliminary data indicate that CD40 stimulation can indeed induce AICD in RCC lines and importantly, may increase susceptibility of the tumor to immune-mediated attack. Assessment of the effects of CD40 stimulation at both cellular and molecular levels will be performed. Specific Aim 2 will examine the mechanisms as to why there is no engagement of CD4+ T cells after combination treatment and how this may impair sustained anti- tumor responses. Preliminary data suggest that the CD4+ T cell undergo AICD after combination treatment due to interferon-gamma resulting in impaired secondary responses. Means to prevent this CD4+ T cell loss with subsequent effects on anti-tumor responses will be examined. Finally, Specific Aim 3 will determine the efficacy of tumor vaccines and removal of inhibitory influences such as regulatory T cells in advanced tumor-bearing mice. Preliminary data indicates that use of tumor vaccines at the time of anti-CD40 and IL-2 treatment greatly augments efficacy resulting in long-term cures. This proposal should yield significant insights, not only in the clinical extrapolation of CD40 stimulation with IL-2, but also in general immune regulation and tumor responses.

晚期癌症患者的治疗选择非常有限。选择性免疫攻击提供了一种对抗传播性疾病的方法。 CD40-CD40L 相互作用已被证明对于产生最佳免疫反应至关重要。我们最近证明，使用激动剂抗体与 IL2 组合刺激 CD40 可以在患有晚期转移性肾细胞癌 (RCC) 和其他实体瘤的小鼠中产生高度协同的抗肿瘤反应。仅使用该组合即可产生显着的保护。这种保护与树突状细胞和肿瘤特异性 CD8+ T 细胞数量的显着增加相关，并且令人惊讶的是，与 CD4+ T 细胞反应无关。我们现在建议描述这些协同抗肿瘤反应的潜在机制并对其进行优化。为了实现这一目标，我们制定了三个具体目标。具体目标 1 将确定 CD40 刺激对肿瘤本身的影响。虽然 CD40 刺激已被证明可诱导多种 B 细胞淋巴瘤的激活诱导细胞死亡 (AICD)，但对实体瘤的影响尚存在争议且不太明确。初步数据表明，CD40 刺激确实可以在 RCC 细胞系中诱导 AICD，而且重要的是，可能会增加肿瘤对免疫介导攻击的敏感性。将在细胞和分子水平上评估 CD40 刺激的效果。具体目标 2 将研究联合治疗后为何 CD4+ T 细胞没有参与的机制，以及这如何损害持续的抗肿瘤反应。初步数据表明，CD4+ T 细胞在联合治疗后由于干扰素-γ 会发生 AICD，导致继发反应受损。将检查防止 CD4+ T 细胞损失及其随后对抗肿瘤反应的影响的方法。最后，具体目标 3 将确定肿瘤疫苗的功效以及消除抑制性影响（例如晚期荷瘤小鼠中的调节性 T 细胞）。初步数据表明，在抗 CD40 和 IL-2 治疗时使用肿瘤疫苗可大大增强疗效，从而实现长期治愈。该提议不仅在 IL-2 刺激 CD40 的临床外推方面，而且在一般免疫调节和肿瘤反应方面都应该产生重要的见解。