Adoptive Immunotherapy for Renal Carcinoma Using Dendritic Cell/Tumor Fusions

点击翻译按钮获取中文摘要

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.