In vivo targeted DC vaccine to activate anti-tumor CTL

体内靶向DC疫苗激活抗肿瘤CTL

基本信息

批准号：
7913511
负责人：
YAN CUI
金额：
$ 27.04万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Successful eradication of solid tumors and metastatic disease by immunotherapy requires systemic and persistent functional anti-tumor cytotoxic T lymphocytes (CTL). Dendritic cells (DC), as the pivotal initiator and regulator of immune responses, have become the major targets and candidates for tumor immunotherapy. However, the therapeutic efficacy of ex vivo manipulated DCs is limited by their inefficient homing to the lymphoid compartments where T cell activation occurs. To enhance the sustained high numbers of activated tumor antigen presenting DCs in relevant lymphoid compartments, we propose that lentiviral vector modified DC progenitors, after transplantation, can provide a constant reservoir for in vivo generation of large numbers of antigen expressing DCs with appropriate activation regimens. We have already demonstrated that these modified DC progenitors, in combination with DC activation regimens markedly activate systemic antigen specific immunity and significantly improve tumor-free survival in the treatment of aggressive, established murine hematological and epithelial tumors carrying a model tumor antigen. Hypothesis: Significant therapeutic benefits in treating solid tumor and metastatic disease can be achieved by using an optimal combination of early DC engraftment progenitors, reduced toxicity of conditioning regimen, fresh lymphocyte infusion, and optimal DC activation regimens to stimulate systemic and sustained CTL activation in the context of weakly immunogenic natural tumor antigens. The Specific Aims will focus on the following aspects to examine the underlying mechanisms that support sustained CTL function and maximal therapeutic efficacy: (1) To test the hypothesis that proper combinations of DC stimulatory and activation regimens will provide not only great number of in vivo derived tumor antigen expressing DCs, but also optimal DC subsets for appropriate cytokine production and class of immune responses. These DCs will dictate the polarization of antigen specific immune responses and support sustained, systemic activation of antigen specific CTL effector function in multiple lymphoid compartments in antigen-naive and antigen-tolerant hosts; (2) To test the hypothesis that the enhanced, systemic CTL activation will result in sustained recruitment of functional tumor specific CTL to multiple tumor draining lymphoid compartments and tumor sites, and thus enable successful treatment of solid tumors and metastatic disease.

描述（由申请人提供）：通过免疫疗法成功消除实体瘤和转移性疾病，需要全身和持续的功能性抗肿瘤细胞毒性T淋巴细胞（CTL）。树突状细胞（DC）作为免疫反应的关键引发剂和调节剂，已成为肿瘤免疫疗法的主要靶标和候选者。然而，离体操纵DC的治疗疗效受到其效率低落到发生T细胞激活的淋巴区室的限制。为了增强相关淋巴区室中持续数量的活化肿瘤抗原，我们提出，移植后慢病毒载体修饰的DC祖细胞可以为体内生成大量的抗原表达DC具有适当的活化激活方案提供恒定的储层。我们已经证明，这些修饰的直流祖细胞与直流活化方案结合使用明显激活了全身抗原特异性免疫，并显着提高了无肿瘤的生存，在治疗携带模型肿瘤抗原的侵略性，既定的鼠血液学和上皮肿瘤的治疗。假设：可以通过使用最佳的DC植入祖细胞的最佳组合，降低调节治疗方案的毒性，新鲜的淋巴细胞输注以及最佳的DC激活方案来刺激全身和持续的CTL自然雌激活，从而实现降低调节方案的毒性，新鲜的淋巴细胞输注和最佳的DC激活方案来刺激弱养剂，从而实现了降低的治疗效果和转移性疾病的显着治疗益处。具体目的将集中在以下各个方面，以检查支持持续的CTL功能和最大治疗功效的潜在机制：（1）测试以下假设：DC刺激和激活方案的适当组合不仅会在体内deriged derive derime dymor抗原抗原表达DCS中不仅提供适当的cytok cytok and cytok cytok，而且还将提供大量的cytok cytok cytok。这些DC将决定抗原特异性免疫反应的极化和支持的抗原特异性CTL效应子功能的全身性激活在多个淋巴机中的抗原和耐药宿主中的极化；（2）测试以下假设：增强的全身性CTL激活将导致功能性肿瘤特异性CTL持续募集到多个肿瘤排出的淋巴样室和肿瘤部位，从而成功治疗实体瘤和转移性疾病。