Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells

使用分泌 IL-12 的肿瘤靶向 T 细胞进行癌症过继免疫治疗

基本信息

批准号：
8444267
负责人：
Renier Joseph Brentjens
金额：
$ 35.87万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444267
关键词：
Address Adoptive Immunotherapy Adverse effects Antibodies Antibody Therapy Antigen Presentation Antigen Receptors Antigen Targeting Autologous Award B-Cell Neoplasm B-Lymphocytes Binding Biology CD19 Antigens CD19 gene CD28 gene CD3 Antigens Cancer Patient Cell physiology Cells Chronic Lymphocytic Leukemia Clinical Clinical Trials Cytolysis Data Detection Disease Down-Regulation Elements Epitopes Failure Funding Future Genes Goals Health Hematopoietic Neoplasms Human Immune Immune system Immunosuppressive Agents In Vitro Institutional Review Boards Interleukin-10 Interleukin-12 Knock-in Mouse Knock-out Laboratories Length Ligands MS4A1 gene Malignant Neoplasms Mediating Modeling Mus Natural Killer Cells Patients Proteins Protocols documentation Publishing Reagent Receptor Gene Recruitment Activity Refractory Regulatory T-Lymphocyte Resistance Role SCID Beige Mouse Safety Signal Transduction Site Solid Neoplasm T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Toxic effect Transgenic Organisms Tumor Antigens Tumor Cell Line Tumor Escape Tumor-Derived Tumor-Infiltrating Lymphocytes Xenograft procedure base cancer cell chemotherapy clinically relevant cytokine design gene therapy genetic manipulation immunogenic improved functioning in vivo killings leukemia neoplastic cell novel pre-clinical receptor rituximab safety study suicide gene suicide vector trafficking tumor tumor eradication tumor microenvironment vector

项目摘要

DESCRIPTION (provided by applicant): T cells may be genetically modified to target antigens expressed on tumor cells through the retroviral insertion of a gene encoding a chimeric antigen receptor (CAR). A CAR is typically composed of a murine antibody- derived tumor-targeted single chain fragment length antibody (scFv) fused to the CD28 co-stimulatory receptor transmembrane and cytoplasmic signaling domains, fused to the cytoplasmic signaling domain of the CD3 6 chain. T cells expressing the resulting CAR gene product subsequently recognize and lyse normal as well as tumor cells which express the targeted antigen. 19-28z is a CAR specific to the CD19 antigen expressed on normal B cells as well as most B cell tumors. Human T cells expressing the 19-28z CAR lyse CD19+ tumor cell lines both in vitro, and in vivo in SCID-Beige mice. Although these data are consistent with the ability of genetic manipulation to overcome tumor cell escape from immune detection, these studies fail to address other potential limitations of this gene-based immune approach. Specifically, prior studies have demonstrated that while genetically targeted T cells are susceptible to inhibition by other factors present in the tumor microenvironment including CD4+ CD25hi regulatory T cells (Tregs) as well as the inhibitory cytokine TGF2. T cells further modified to express the IL-12 cytokine become resistant to these inhibitory factors. Recent studies have demonstrated a remarkable resistance of human effector T cells to inhibition by either cultured autologous Tregs or exogenous TGF2. A clinically relevant syngeneic and immune competent hCD19+ tumor model has been developed in the laboratory utilizing transgeneic C57BL6 murine CD19 knockout, hCD19 knockin (mCD19-/- hCD19+/-) mice to 1) better define the role of the immunosuppressive microenvironment, 2) assess the role of IL-12 secreting genetically targeted T cells in modulating this microenvironment, and 3) study the safety as well as develop and test suicide gene approaches to selectively delete modified T cells following complete tumor eradication. Aim1 of this proposal will test the hypothesis that IL-12 secreting targeted T cells are resistant to prominent suppressive factors present in the tumor microenvironment including Tregs, the inhibitory cytokines TGF2 and IL-10, and PD-1 activation on T cells by PD-L1 expressed within the tumor microenvironment. Aim 2 of this proposal will test the hypothesis that localized IL-12 secretion by targeted T cells will recruit or activate other host immune elements, including natural killer cells as well as anergic TILs, thereby broadening the anti-tumor immune repertoire. Aim 3 of the protocol will study the potential side effects of IL-12 secreting targeted T cells in the immune competent host, and further test a novel suicide gene approach designed to eradicate adoptively transferred T cells following complete tumor eradication thereby enhancing the safety profile of this therapeutic approach. Data generated from these studies will ultimately serve to provide the rationale of utilizing IL-12 secreting tumor targeted T cells in future clinical trials of adoptive immunotherapy in patients with both hematologic and solid tumor malignancies.

描述（由申请人提供）：T细胞可以通过逆转录病毒插入编码嵌合抗原受体（CAR）的基因进行基因修饰，以靶向肿瘤细胞上表达的抗原。 CAR 通常由鼠源抗体衍生的肿瘤靶向单链片段长度抗体 (scFv) 组成，该抗体与 CD28 共刺激受体跨膜和细胞质信号结构域融合，并与 CD3 6 链的细胞质信号结构域融合。表达所得 CAR 基因产物的 T 细胞随后识别并裂解表达目标抗原的正常细胞和肿瘤细胞。 19-28z 是一种针对正常 B 细胞以及大多数 B 细胞肿瘤上表达的 CD19 抗原的 CAR。表达 19-28z CAR 的人类 T 细胞在体外和 SCID-Beige 小鼠体内裂解 CD19+ 肿瘤细胞系。尽管这些数据与基因操作克服肿瘤细胞逃避免疫检测的能力一致，但这些研究未能解决这种基于基因的免疫方法的其他潜在局限性。具体而言，先前的研究表明，虽然基因靶向 T 细胞容易受到肿瘤微环境中存在的其他因素的抑制，包括 CD4+ CD25hi 调节性 T 细胞 (Treg) 以及抑制性细胞因子 TGF2。经过进一步修饰以表达 IL-12 细胞因子的 T 细胞对这些抑制因子产生抗性。最近的研究表明，人类效应 T 细胞对培养的自体 Tregs 或外源 TGF2 的抑制具有显着的抵抗力。实验室利用转基因 C57BL6 鼠 CD19 敲除、hCD19 敲入 (mCD19-/- hCD19+/-) 小鼠开发了临床相关的同基因和免疫能力 hCD19+ 肿瘤模型，以 1) 更好地定义免疫抑制微环境的作用，2) 评估分泌基因靶向 T 细胞的 IL-12 在调节这种微环境中的作用，以及 3) 研究安全性以及开发和测试自杀完全根除肿瘤后选择性删除修饰的 T 细胞的基因方法。该提案的目标 1 将检验以下假设：分泌 IL-12 的靶向 T 细胞对肿瘤微环境中存在的重要抑制因子具有抵抗力，包括 Tregs、抑制性细胞因子 TGF2 和 IL-10，以及 PD-1 对 T 细胞的激活。 L1 在肿瘤微环境中表达。该提案的目标 2 将检验以下假设：靶向 T 细胞的局部 IL-12 分泌将招募或激活其他宿主免疫元件，包括自然杀伤细胞以及无反应性 TIL，从而扩大抗肿瘤免疫库。该协议的目标 3 将研究分泌 IL-12 的靶向 T 细胞在具有免疫能力的宿主中的潜在副作用，并进一步测试一种新颖的自杀基因方法，该方法旨在在完全根除肿瘤后根除过继转移的 T 细胞，从而增强这种治疗方法。这些研究产生的数据最终将为在血液系统和实体瘤恶性肿瘤患者的过继免疫治疗的未来临床试验中利用分泌IL-12的肿瘤靶向T细胞提供理论依据。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.

CD19 定向嵌合抗原受体 T 细胞治疗华氏巨球蛋白血症：临床前模型和初步临床经验。

DOI：
发表时间：
2022-02
期刊：
影响因子：
0
作者：
Palomba, M Lia;Qualls, David;Monette, Sebastien;Sethi, Shenon;Dogan, Ahmet;Roshal, Mikhail;Senechal, Brigitte;Wang, Xiuyan;Rivière, Isabelle;Sadelain, Michel;Brentjens, Renier J;Park, Jae H;Smith, Eric L
通讯作者：
Smith, Eric L

Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells.

使用自体嵌合抗原受体修饰的肿瘤靶向 T 细胞对 B 细胞恶性肿瘤进行过继免疫治疗。