Development of GIFT4: a B cell focused immunotherapy for cancer

GIFT4 的开发：针对癌症的 B 细胞免疫疗法

基本信息

批准号：
9345070
负责人：
PAUL GUYRE
金额：
$ 99.91万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-12 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9345070
关键词：
Adoptive Cell Transfers Adoptive Transfer Animals Antigen Presentation Autopsy B-Lymphocytes Biological Biological Assay Biological Markers Cancer Model Cancer Patient Cells Clinical Clinical Trials Clonal Expansion Data Development Dose Electrocardiogram Evaluation Excretory function Fermentation Goals Grant Granzyme Guidelines Human Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Surveillance Immunotherapeutic agent Immunotherapy In Vitro Injectable Injection of therapeutic agent Interferon Type II Interleukin-2 Interleukin-6 Investigational Drugs Investigational New Drug Application Malignant Neoplasms Maximum Tolerated Dose Mediating Melanoma Cell Metabolism Minority Modeling Monitor Mus Organ Pathology Patients Phase Phenotype Preparation Process Production Proliferating Property Proteins Protocols documentation Research Resistance development Rodent Safety Small Business Innovation Research Grant Solid Neoplasm System T cell response T-Lymphocyte Testing Toxic effect Toxicology Xenograft procedure Yeasts absorption biomarker identification cancer cell cancer immunotherapy cancer survival chimeric antigen receptor commercialization cytokine efficacy study experimental study flasks granulysin human subject immunogenicity improved in vivo inhibitor/antagonist killings melanoma mouse model neoplastic cell novel partial response preclinical development preclinical safety response safety study tumor tumor growth tumor microenvironment

项目摘要

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.

项目概要我们的目标是开发一种新的免疫疗法来治疗黑色素瘤，并可能开发出多种治疗方法尽管免疫系统的监视消除了某些肿瘤细胞中的癌细胞。已经开发出多种机制来逃避免疫识别，这通常会导致肿瘤生长。免疫检查点抑制剂（例如伊匹单抗、纳武单抗和派姆单抗）和细胞免疫疗法（例如过继细胞转移和 CAR（嵌合抗原受体）T 细胞）在然而，即使是最有希望的疗法也只能对有限范围的癌症有效。并且仅适用于少数患者（例如 PD-1 抑制剂的缓解率约为 25-40%）。与显着的毒性相关，肿瘤——尤其是实体瘤——最终会产生耐药性。 B 细胞作为抗肿瘤免疫疗法的潜力在很大程度上尚未开发。然而，B 细胞构成癌症浸润免疫细胞的一部分，并且具有抗肿瘤特性包括产生肿瘤抑制细胞因子和增强肿瘤杀伤 T 细胞反应。肿瘤微环境中 B 细胞的存在与癌症患者的长期生存相关。该应用程序的重点是推进我们的临床前开发，为后续的研究做好准备我们将向 FDA 申请新药研究 (IND) 的最佳有效剂量。小鼠癌症模型中的 GIFT4；在适当的模型中组装毒理学包并进行优化表达并开发发酵和大规模纯化方案将成功商业化。最终在多种癌症适应症中提供深远的抗肿瘤免疫治疗益处，特别是那些免疫系统减弱、对其他免疫疗法没有反应的患者。