Adoptive Immunotherapy for Renal Carcinoma Using Dendritic Cell/Tumor Fusions

目前对转移性肾细胞癌（RCC）的治疗是不充分的，因为该疾病对化疗耐药。 标准化疗药物。相反，舒尼替尼，一种口服酪氨酸激酶抑制剂， 血管生成特性，代表了相对于现有疗法的显著进步。虽然大多数患者 出现疾病消退或稳定，反应不完全且持续时间短暂。因此，在本发明中， 迫切需要开发进一步增强临床反应的疗法。RCC展示了一种独特的 对免疫疗法的敏感性。我们已经开发了一种肿瘤疫苗，其中树突状细胞（DC）是 与RCC细胞融合，导致广泛的肿瘤抗原的有效呈递。疫苗接种 已经导致免疫学和临床应答，但是效力受到免疫抑制环境的限制 部分由调节性T细胞的存在和表达的增加介导的 抑制性配体PDL 1克服抑制的一个策略是刺激肿瘤反应性细胞 离体用作过继免疫疗法。我们发现了一种新的策略， 活化的抗肿瘤T细胞，并通过用 DC/肿瘤融合，然后是抗CD 3/CD 28。我们还表明，融合疫苗的反应， 通过暴露于舒尼替尼治疗进一步增强，舒尼替尼治疗消耗调节性T细胞并抑制PDL 1 RCC细胞的表达。因此，一种有希望的策略是联合使用舒尼替尼和 使用DC/RCC训练的和抗CD 3/CD 28扩增的肿瘤反应性T细胞的过继免疫疗法。在 在这个项目中，我们将进行一项I/II期临床试验，在该试验中，第一批转移性RCC患者将被纳入研究。 将接受由DC/RCC融合和抗CD 3/CD 28刺激的T细胞，并使用 DC/RCC融合。研究了活化T细胞的毒性、最大耐受量（MTD）、免疫学效应和 将确定临床反应。一个扩大的II期患者队列将接受DC/RCC治疗 受教育的和抗CD 3/CD 28扩增的T细胞与舒尼替尼疗法联合。患者将接受 用DC/RCC融合物加强疫苗接种以进一步扩大反应。治疗诱导 抗肿瘤免疫应答，表现为活化的T细胞的存在增加， 将测定RCC和肿瘤特异性抗原，并与用活化T细胞观察到的抗原进行比较 一个人免疫应答将与调节性T细胞和肿瘤的循环水平相关， PDL 1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.