In vivo targeted DC vaccine to activate anti-tumor CTL

描述(申请人提供)：通过免疫疗法成功根除实体瘤和转移性疾病需要系统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细胞。然而，体外操纵的DC的治疗效果是有限的，因为它们不能有效地归巢到发生T细胞激活的淋巴室。为了增强相关淋巴室中持续高数量的激活的肿瘤抗原提呈的DC，我们建议慢病毒载体修饰的DC前体细胞移植后，可以通过适当的激活方案为体内大量表达抗原的DC提供恒定的储存库。我们已经证明，这些改良的DC前体细胞与DC激活方案相结合，显著激活了系统抗原特异性免疫，并显著提高了携带模型肿瘤抗原的侵袭性、已建立的小鼠血液和上皮性肿瘤的无瘤生存率。假说：在实体瘤和转移性疾病的治疗中，使用早期DC植入祖细胞、降低预适应方案的毒性、新鲜淋巴细胞输注和最佳DC激活方案的最佳组合可以在弱免疫原性天然肿瘤抗原的背景下刺激系统和持续的CTL激活，从而获得显著的治疗益处。具体目的将集中在以下几个方面，以研究支持持续的CTL功能和最大治疗效果的潜在机制：(1)检验DC刺激和激活方案的适当组合将不仅提供大量体内来源的表达肿瘤抗原的DC的假设，而且还将提供合适的DC亚群以产生适当的细胞因子和免疫应答。这些树突状细胞将决定抗原特异性免疫反应的极化，并支持抗原初始和抗原耐受宿主的多个淋巴隔室中持续、系统地激活抗原特异性CTL效应器功能；(2)检验这样一种假设，即增强的系统性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隔间和肿瘤部位，从而使实体瘤和转移性疾病能够成功治疗。

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.