Adoptive Immunotherapy for Renal Carcinoma Using Dendritic Cell/Tumor Fusions

目前对转移性肾细胞癌(RCC)的治疗是不够的，因为这种疾病对 标准化疗药物。相比之下，舒尼替尼是一种口服酪氨酸激酶抑制剂，具有抗 血管生成特性，代表着比以前的治疗方法有了显著的进步。尽管大多数患者 经历疾病消退或稳定，反应不完全且持续时间短暂。因此， 开发治疗方法以进一步增强临床反应是当务之急。RCC展示了一种独特的 对基于免疫的治疗敏感。我们已经开发出一种肿瘤疫苗，其中树突状细胞(DC) 与肾细胞癌细胞融合，可有效呈递多种肿瘤抗原。接种疫苗 已导致免疫学和临床反应，但疗效受到免疫抑制环境的限制 部分由调节性T细胞的存在和表达增加所介导的荷瘤患者的 抑制配体PDL1。克服抑制的一种策略是刺激肿瘤反应细胞 用于过继免疫治疗的体外实验。我们发现了一种新的战略，可以显著扩大 激活抗肿瘤T细胞，并通过顺序刺激T细胞来限制调节性T细胞的影响 DC/肿瘤融合后抗CD3/CD28。我们还表明，融合疫苗的反应可以是 接受舒尼替尼治疗可耗尽调节性T细胞并抑制PDL1，从而进一步增强 肾细胞癌细胞表达。因此，一个有希望的策略将是联合使用舒尼替尼和 DC/RCC教育和抗CD3/CD28过继免疫治疗可扩增肿瘤反应性T细胞。在……里面 在这个项目中，我们将进行L/111期临床试验，在该试验中，第一批转移性肾细胞癌患者 将接受DC/RCC融合和抗CD3/CD28刺激的T细胞，并加强疫苗接种 DC/RCC融合。激活的T细胞的毒性、最大耐受量(MTD)、免疫效应和 临床反应将被确定。扩大的II期患者队列将接受DC/RCC治疗 教育和抗CD3/CD28扩增的T细胞与舒尼替尼联合治疗。患者将接受 通过DC/RCC融合加强疫苗接种，以进一步放大应答。治疗诱导的能力 抗肿瘤免疫反应，表现为活化的T细胞识别 RCC和肿瘤特异性抗原将被测定，并与活化的T细胞观察到的相比较 独自一人。免疫反应将与调节性T细胞和肿瘤的循环水平相关 PDL1的DC/RCC表达。

Current therapy for metastatic renal cell carcinoma (RCC) is inadequate as the disease is resistant to Standard chemotherapeutic agents. In contrast, sunitinib, an oral tyrosine kinase inhibitor with anti¿ angiogenic properties, represents a significant advance over prior therapies. Although a majority of patients experience disease regression or stabilization, responses are incomplete and of transient duration. As such, it is imperative to develop therapies to further augment clinical responses. RCC demonstrates a unique sensitivity to immune based therapy. We have developed a tumor vaccine in which dendritic cells (DC) are fused with RCC cells resulting in the effecfive presentation of a broad array of tumor antigens. Vaccination has resulted in immunologic and clinical responses but efficacy is limited by the immunosuppressive milieu of the tumor bearing patient mediated in part by the increased presence of regulatory T cells and expression of the inhibitory ligand, PDL1. One strategy to overcome inhibifion is the stimulation of tumor reactive cells ex vivo for use as adoptive immunotherapy. We have discovered a novel strategy to markedly expand activated anti-tumor T cells and limit the infiuence of regulatory T cells by sequentially stimulating T cells with DC/tumor fusions followed by anti-CD3/CD28. We have also shown that fusion vaccine responses can be further augmented by exposure to sunitinib therapy which depletes regulatory T cells and suppresses PDL1 expression by RCC cells. As such, a promising strategy would be the combined use of sunitinib and adoptive immunotherapy with DC/RCC educated and anti-CD3/CD28 expanded tumor reactive T cells. In this project, we will conduct a phase l/ll clinical trial in which the first cohort of patients with metastatic RCC will receive T cells stimulated by DC/RCC fusions and anti-CD3/CD28 and boosting vaccinations with DC/RCC fusions. The toxicity, maximum tolerated dose (MTD) of activated T cells, immunologic effect, and clinical response will be determined. An expanded phase II cohort of patients will be treated with DC/RCC educated and anti-CD3/CD28 expanded T cells in conjunction with sunitinib therapy. Patients will undergo boosting vaccinations with DC/RCC fusions to further amplify response. The capacity of therapy to induce anti-tumor immune response as manifested by the increased presence of activated T cells that recognize RCC and tumor specific antigens will be determined and compared to that observed with activated T cells alone. Immunologic response will be correlated with circulating levels of regulatory T cells and tumor and DC/RCC expression of PDL1.