In vivo targeted DC vaccine to activate anti-tumor CTL

描述（由申请人提供）：通过免疫治疗成功根除实体瘤和转移性疾病需要全身和持久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，体外操纵dc的治疗效果受到其不能有效归巢到T细胞活化发生的淋巴细胞室的限制。为了增强相关淋巴室中持续高数量的肿瘤抗原呈递树突状细胞的活性，我们提出慢病毒载体修饰的树突状细胞祖细胞在移植后，可以通过适当的激活方案，为体内产生大量表达抗原的树突状细胞提供一个恒定的储存库。我们已经证明，这些改良的DC祖细胞与DC激活方案结合，在治疗携带模型肿瘤抗原的侵袭性、已建立的小鼠血液学和上皮肿瘤时，显著激活全身抗原特异性免疫，显著提高无瘤生存率。假设：在弱免疫原性天然肿瘤抗原的背景下，使用早期DC植入祖细胞、降低调节方案的毒性、新鲜淋巴细胞输注和最佳DC激活方案的最佳组合来刺激全身和持续的CTL激活，可以在治疗实体瘤和转移性疾病中获得显著的治疗效果。具体目标将集中在以下方面，以检查支持持续CTL功能和最大治疗效果的潜在机制：(1)验证DC刺激和激活方案的适当组合不仅可以提供大量体内衍生的肿瘤抗原表达DC，还可以提供最佳的DC亚群，以适当的细胞因子产生和免疫反应类别。这些dc将决定抗原特异性免疫反应的极化，并支持抗原特异性CTL效应功能在抗原初始和抗原耐受宿主的多个淋巴细胞室中持续、系统地激活；(2)验证增强的系统性CTL激活将导致功能性肿瘤特异性CTL持续募集到多个肿瘤引流淋巴室和肿瘤部位，从而成功治疗实体瘤和转移性疾病的假设。

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.