In vivo targeted DC vaccine to activate anti-tumor CTL

描述（由申请方提供）：通过免疫疗法成功根除实体瘤和转移性疾病需要全身性和持续性功能性抗肿瘤细胞毒性T淋巴细胞（CTL）。树突状细胞（DC）作为免疫应答的关键启动者和调节者，已成为肿瘤免疫治疗的主要靶点和候选者。然而，离体操作的DC的治疗功效受限于它们向发生T细胞活化的淋巴区室的低效归巢。为了增强相关淋巴区室中持续高数量的活化的肿瘤抗原呈递DC，我们提出慢病毒载体修饰的DC祖细胞在移植后可以提供恒定的储库，用于在体内产生大量的抗原表达DC，并具有适当的活化方案。我们已经证明，这些修饰的DC祖细胞与DC活化方案组合显著激活全身抗原特异性免疫，并在治疗携带模型肿瘤抗原的侵袭性、已建立的鼠血液和上皮肿瘤中显著提高无肿瘤存活率。假设：在治疗实体瘤和转移性疾病中的显著治疗益处可以通过使用早期DC植入祖细胞、降低的预处理方案毒性、新鲜淋巴细胞输注和最佳DC活化方案的最佳组合来实现，以在弱免疫原性天然肿瘤抗原的背景下刺激全身性和持续的CTL活化。具体目的将集中在以下方面来研究支持持续CTL功能和最大治疗功效的潜在机制：（1）验证DC刺激和活化方案的适当组合不仅可以提供大量体内衍生的表达肿瘤抗原的DC，而且可以提供用于适当细胞因子产生和免疫应答类别的最佳DC亚群的假设。这些DC将决定抗原特异性免疫应答的极化，并支持抗原未处理和抗原耐受宿主中多个淋巴区室中抗原特异性CTL效应子功能的持续、系统活化;（2）为了检验增强的系统性CTL活化将导致功能性肿瘤特异性CTL持续募集到多个肿瘤引流淋巴区室和肿瘤部位的假设，从而能够成功治疗实体瘤和转移性疾病。

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.