Development of a B Cell Based Vaccine for the Treatment of Newly Diagnosed Malignant Gliomas

项目3：概要 免疫疗法已经显著改善了许多癌症患者的临床结果。然而，大多数胶质母细胞瘤 (GBM)到目前为止，病人还没有从免疫干预中受益。探索替代方法， 为了增强抗GBM的免疫力，我们开发了一种基于B细胞的疫苗（BVax），其由4-1BBL+ B细胞组成 用CD 40激动、BAFF和IFNg刺激活化。在我们的临床前研究中，BVax迁移到关键的次要 淋巴器官，并精通抗原交叉呈递，促进肿瘤的存活和功能， 浸润性CD 8 + T细胞。此外，BVax产生与肿瘤反应的免疫球蛋白（体液免疫应答）。 这些免疫球蛋白引起了有效的治疗效果。放射、BVax、CD 8 T细胞和PD-L1的组合 阻断在80%的治疗的荷瘤动物中实现了肿瘤根除。本研究旨在翻译 BVax用于治疗新诊断的恶性胶质瘤。为了在临床上有效地实施这种疗法，我们 建议进行IND使能研究，以生产自体BVax和CD 8 T细胞（目标1）。经FDA批准， 我们的目标是进行首次人体BVax试验（目标2），并评估对免疫应答的影响（目标3）。我们 假设所提出的自体细胞疗法在引发保护性抗GBM免疫方面是安全有效的 通过细胞和体液免疫反应。总的来说，我们的研究提供了一种新的替代目前 免疫力接近。

PROJECT 3: SUMMARY Immunotherapy has significantly improved the clinical outcome of many cancer patients. However, most glioblastoma (GBM) patients have not, so far, benefited from immunotherapeutic intervention. To explore alternative ways to potentiate the anti-GBM immunity, we've developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism, BAFF, and IFNg stimulation. In our preclinical study, BVax migrates to critical secondary lymphoid organs and is proficient at antigen cross-presentation, promoting the survival and functionality of tumor- infiltrating CD8+ T cells. In addition, BVax produces immunoglobulins (humoral immune response) reactive to the tumor. These immunoglobulins elicited a potent therapeutic effect. A combination of radiation, BVax, CD8 T cells and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This research proposal aims to translate BVax to the clinic to treat newly diagnosed malignant gliomas. To effectively implement this therapy in the clinic, we propose to perform IND-enabling studies to manufacture autologous BVax and CD8 T cells (Aim 1). Upon FDA approval, we aim to conduct a first-in-human BVax trial (Aim 2) and evaluate the effect on the immune response (Aim 3). We hypothesize that the proposed autologous cellular therapy is safe and effective at eliciting protective anti-GBM immunity via cellular and humoral immune responses. Overall, our study provides a novel alternative to current immunotherapeutic approaches.