Development of GIFT4: a B cell focused immunotherapy for cancer

项目摘要 我们的目标是开发一种新的免疫疗法来治疗黑色素瘤，并可能开发出一系列广泛的免疫疗法。 肿瘤的尽管免疫系统的监视在某些情况下消除了癌细胞， 已经发展了多种机制来逃避免疫识别，通常导致肿瘤生长。 免疫检查点抑制剂（如易普利姆玛、纳武单抗和派姆单抗）和细胞免疫疗法 (e.g.过继性细胞转移和CAR（嵌合抗原受体）T细胞）显示出显著的疗效， 进行临床试验然而，即使是最有希望的治疗方法也只能对有限范围的癌症有效。 仅适用于少数患者（例如，PD-1抑制剂的缓解率约为25-40%）。此外，他们可以 与显著的毒性相关，并且肿瘤-特别是实体瘤-最终产生耐药性。 B细胞作为抗肿瘤免疫治疗剂的潜力在很大程度上仍未开发。 然而，B细胞构成癌浸润免疫细胞的一部分，并且它们具有抗肿瘤特性 包括产生肿瘤抑制性细胞因子和增强肿瘤杀伤T细胞应答。持续增 肿瘤微环境中B细胞的存在与癌症患者的长期存活相关。 该申请的重点是推进我们的临床前开发，为随后的 向FDA提交研究性新药（IND）申请。我们将确定最佳的有效剂量 小鼠癌症模型中的GIFT 4;在适当的模型中组装毒理学包并优化 表达和开发发酵和大规模纯化方案。成功的商业化将 最终在多种癌症适应症中提供深刻的抗肿瘤免疫益处， 特别是那些以免疫系统减弱而对其它免疫疗法无反应为特征的疾病。

Project Summary Our goal is to develop a novel immunotherapy for the treatment of melanoma, and potentially a wide array of tumors. Although surveillance by the immune system eliminates cancer cells in some instances, tumor cells have developed a variety of mechanisms to escape immune recognition often resulting in tumor outgrowth. Immune checkpoint inhibitors (e.g. ipilimumab, nivolumab, and pembrolizumab) and cellular immunotherapies (e.g. adoptive cell transfer and CAR (chimeric antigen receptor) T cells) are showing dramatic efficacy in on- going clinical trials. However, even the most promising therapies are effective for a limited range of cancers and only for a minority of patients (e.g. response rates with PD-1 inhibitors are ~25-40%). Moreover, they can be associated with significant toxicities, and tumors – especially solid tumors – eventually develop resistance. The potential of B cells as anti-tumor immunotherapeutics has, to a large extent, remained untapped. Nevertheless, B cells constitute part of the cancer-infiltrating immune cells and they have anti-tumor properties including production of tumor-suppressive cytokines and enhancing tumor-killing T cell response. Indeed, the presence of B cells in the tumor microenvironment is correlated with long-term survival for cancer patients. This application is focused on advancing our preclinical development in preparation for a subsequent Investigational New Drug (IND) application to the FDA. We will determine the optimal efficacious dose of GIFT4 in murine models of cancer; assemble a toxicology package in appropriate models and optimize exprssion and develop fermentation and large-scale purification protocols. Successful commercialization would ultimately provide profound anti-tumor immunotherapeutic benefits in a wide variety of cancer indications, particularly those characterized by a weakened immune system that do not respond to other immunotherapies.