Giloma Vaccines in Combination with Poly-ICLC

描述(由申请人提供)：我们的主要目标是开发安全和有效的免疫治疗策略来治疗中枢神经系统(CMS)肿瘤，如恶性胶质瘤。我们认为，外周疫苗诱导的系统性抗肿瘤免疫反应应与增强疫苗诱导的效应细胞在中枢神经系统肿瘤部位的归巢和功能的方法相结合。为此，我们认为聚赖氨酸和羧甲基纤维素稳定的多肌苷多胞酸(Poly-ICLC)是一种诱人的诱导炎性细胞因子/趋化因子(如干扰素-α)的药物。在GL261小鼠胶质瘤中，我们将评估我们的假设，即Poly-ICLC将增强胶质瘤相关抗原(GAA)来源的细胞毒性T淋巴细胞(CTL)表位的外周疫苗的效果，不仅促进GAA特异性CTL的增殖，而且促进T细胞表达归巢受体/整合素分子，这些T细胞对其趋向性和向中枢神经系统肿瘤的渗透至关重要，例如表达非常晚的抗原[VLA]-4。然而，由于肿瘤诱导的免疫抑制机制，GAA疫苗和PolyICLC的联合治疗效果可能仍然不佳，例如诱导吲哚胺2，3双加氧酶(IDO)，这可能是由PolyICLC给药触发的。因此，我们将确定对这些机制的具体封锁是否能够提高组合办法的效力。尽管我们相信，我们建议的GAA靶向策略将在没有显著的中枢神经系统自身免疫的情况下安全地实施，但我们也将仔细确定是否没有自身免疫性脑炎。越来越清楚的是，单一疗法在癌症环境中是次优的，如果要使用这些方法获得显著的临床益处，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方案。我们的中心假设是，已经过临床评估的Poly-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进行这种方法的前瞻性临床试验提供有价值的信息。我们的具体目标是：特定目标1：通过增强抗胶质瘤CTL的诱导及其对中枢神经系统肿瘤的侵袭，确定PolyICLC治疗能否作为外周抗CNS肿瘤疫苗的有效佐剂。特定目标2：通过对抗CNS微环境中的代偿性、抑制性免疫，开发策略来提高GAA-DC疫苗和PolyICLC联合治疗的效果。

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.