TCR Affinity and Therapeutic Efficacy of T Cells

描述（由申请人提供）：人类肿瘤表达的T细胞抗原的鉴定导致了旨在增强针对其肿瘤的宿主免疫应答的临床试验（综述见1-4）。癌症疫苗策略包括抗原肽、负载肽的树突细胞、重组腺病毒、牛痘病毒和质粒DNA。尽管有接种疫苗的证据，但很少有临床反应的报道。此外，有临床反应的患者通常没有接种疫苗的证据。我们最近描述了一种TCR基因转移治疗策略，旨在为任何患者提供自体肿瘤反应性T细胞的来源，而无论其免疫状态如何。本提案的主要目标是使用人类黑色素瘤的动物模型确定TCR基因修饰的T细胞可以安全地施用并且具有抗肿瘤功效。我们还将确定TCR亲和力、肿瘤抗原疫苗和IL-2如何影响体内TCR基因修饰的T细胞的安全性和有效性。除了安全性和有效性外，我们还将使用我们开发的灵敏PCR检测方法来解决关于荷瘤小鼠中过继转移T细胞命运的相关问题，这些问题在癌症患者中不易解决。成功完成拟议的研究将使我们能够为晚期癌症患者设计更好的免疫治疗策略。

DESCRIPTION (provided by applicant): The identification of T cell antigens expressed by human tumors has led to the clinical trials designed to boost the host immune response against their tumors (reviewed by 1-4). Cancer vaccine strategies include antigenic peptides, peptide loaded dendritic cells, recombinant adenoviruses, vaccinia viruses, and plasmid DNA. Despite evidence of vaccination, very few clinical responses have been reported. Furthermore, those patients which had a clinical response generally have no evidence of vaccination. We have recently described a TCR gene transfer a treatment strategy designed to provide a source of autologous tumor reactive T cell to any patient regardless of their immune status. The primary goal of this proposal is to determine TCR gene modified T cells can be safely administered and have anti-tumor efficacy using an animal model for human melanoma. We will also determine how TCR affinity, tumor antigen vaccines, and IL-2 impacts on the safety and efficacy of TCR gene modified T cells in vivo. In addition to safety and efficacy, we will use using sensitive PCR assays we developed to address relevant questions regarding the fate of adoptively transferred T cells in tumor bearing mice which are not easily addressed in cancer patients. The successful completion of the proposed studies will enable us to design better immunotherapy treatment strategies for patients with advanced cancer.