Giloma Vaccines in Combination with Poly-ICLC

描述（由申请人提供）：我们的主要目标是为中枢神经系统（CMS）肿瘤（如恶性胶质瘤）开发安全有效的免疫治疗策略。我们认为外周疫苗系统性诱导抗肿瘤免疫应答应与增强疫苗诱导效应细胞在中枢神经系统肿瘤部位的归巢和功能的方式相结合。为此，我们相信用聚赖氨酸和羧甲基纤维素稳定的聚肌苷-多胞酸（poly-ICLC）是一种具有诱导炎性细胞因子/趋化因子如干扰素(IFN)- α的能力的有吸引力的药物。使用GL261小鼠胶质瘤，我们将评估我们的假设，即poly-ICLC将增强外周胶质瘤相关抗原（GAA）衍生的细胞毒性T淋巴细胞（CTL）表位接种的效果，不仅可以促进GAA特异性CTL的增殖，还可以促进T细胞的归巢受体/整合素分子表达，这对于它们的趋向性和浸润到中枢神经系统肿瘤至关重要，如极迟抗原[VLA]-4的表达。然而，由于肿瘤诱导的免疫抑制机制，如吲哚胺2,3双加氧酶（IDO）的诱导，gaa疫苗和多聚iclc联合方法的治疗效果可能仍然不理想，多聚iclc可能会触发该机制。因此，我们将确定这些机制的特异性阻断是否可以提高组合方法的功效。尽管我们相信我们提出的gaa靶向策略将在没有显著cns自身免疫的情况下安全进行，但我们也将仔细确定是否存在自身免疫性脑炎。越来越清楚的是，单一模式的治疗方法在癌症治疗中不是最优的，如果要使用这些方法获得显著的临床效益，必须前瞻性地开发在多个水平上协调影响免疫系统的联合治疗方案。我们的中心假设是，先前已进行临床评估的多聚iclc可以有效地与gaa特异性疫苗策略以及其他免疫机制的调节相结合，从而提供更大的治疗效果指数（与单一药物方案相比）。这些临床前研究将为我们在胶质瘤患者中使用该方法的前瞻性临床试验提供有价值的信息。我们的具体目的是：特异性目的1：通过增强抗胶质瘤ctl的诱导及其随后对中枢神经系统肿瘤的浸润，确定poly-ICLC治疗是否可以作为外周抗中枢神经系统肿瘤疫苗的有效“佐剂”。特异性目的2：制定策略，通过抵消中枢神经系统微环境中的代偿性、抑制性免疫来提高gaa - dc疫苗和poly-ICLC联合治疗的疗效。

DESCRIPTION (provided by applicant): Our primary goal is to develop safe and effective immunotherapy strategies for central nervous system (CMS) tumors, such as malignant gliomas. We believe that the systemic induction of anti-tumor immune responses by peripheral vaccines should be combined with modalities that enhance the homing of, and the function of vaccine-induced effector cells within CNS tumor sites. To this end, we believe that polyinosinic-polycytidylic acid stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) is an attractive agent exhibiting the capability to induce inflammatory cytokines/chemokines such as interferon (IFN)-alpha. Using GL261 mouse glioma, we will evaluate our hypothesis that poly-ICLC will enhance the effect of peripheral vaccinations with glioma-associated antigen (GAA)-derived, cytotoxic T lymphocyte (CTL)-epitopes by promoting not only the proliferation of GAA-specific CTLs, but also the promotion of homing receptor/integrin molecule expression by T cells that are critical for their tropism and infiltration into the CNS tumors, such as expression of very late antigen [VLA]-4. However, the therapeutic efficacy of the combination approach with GAA-vaccine and poly-ICLC may remain suboptimal due to tumor-induced immuno-suppressive mechanisms, such as induction of Indoleamine 2,3 dioxygenase (IDO), which may be triggered by poly-ICLC administration. We will therefore determine whether specific blockade of these mechanisms can improve the efficacy of the combinational approach. Even though we believe that our proposed GAA-targeted strategies will be carried out safely without significant CNS-autoimmunity, we will also carefully determine the absence of auto-immune encephalitis. It is becoming increasingly clear that single modality therapies are sub-optimal in the cancer setting and that combinational regimens which coordinately impact the immune system at multiple levels must be prospective^ developed if significant clinical benefit is to be achieved using such approaches. Our central hypothesis is that poly-ICLC, which has been previously clinically evaluated, can be effectively combined with GAA-specific vaccine strategies as well as modulation of other immunological mechanisms, thereby providing a greater index of therapeutic efficacy (versus single-agent regimens). These preclinical studies will provide us with valuable information for our prospective clinical trials with this approach in patients with glioma. Our specific aims are: Specific Aim 1: To determine whether poly-ICLC treatment can serve as an effective "adjuvant" to peripheral anti-CNS tumor-vaccines by enhancing the induction of anti-glioma CTLs and their consequent infiltration of CNS tumors Specific Aim 2: To develop strategies to improve the efficacy of GAA-DC-vaccines and poly-ICLC co-treatment by counteracting the compensatory, suppressive immunity within the CNS microenvironment.