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

• 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
• 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

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）：通过逆转录病毒插入编码嵌合抗原受体（CAR）的基因，可以对T细胞进行遗传修饰，以靶向肿瘤细胞上表达的抗原。CAR通常由与CD 28共刺激受体跨膜和胞质信号传导结构域融合的鼠抗体衍生的肿瘤靶向单链片段长度抗体（scFv）组成，所述CD 28共刺激受体跨膜和胞质信号传导结构域与CD 36链的胞质信号传导结构域融合。表达所得CAR基因产物的T细胞随后识别并裂解表达靶向抗原的正常细胞以及肿瘤细胞。19- 28 z是对在正常B细胞以及大多数B细胞肿瘤上表达的CD 19抗原特异性的CAR。表达19- 28 z CAR的人T细胞在体外和体内在SCID-米色小鼠中裂解CD 19+肿瘤细胞系。尽管这些数据与遗传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。具体地，先前的研究已经证明，虽然遗传靶向的T细胞易受肿瘤微环境中存在的其他因子的抑制，包括CD 4 + CD 25 hi调节性T细胞（TGF 2）以及抑制性细胞因子TGF 2。进一步修饰以表达IL-12细胞因子的T细胞变得对这些抑制因子具有抗性。最近的研究表明，人效应T细胞对培养的自体TGF 2或外源性TGF 2的抑制具有显著的抗性。利用转基因C57 BL 6鼠CD 19敲除、hCD 19敲入和hCD 19基因敲除，（mCD 19-/-hCD 19 +/-）小鼠的免疫抑制作用，以1）更好地定义免疫抑制微环境的作用，2）评估分泌IL-12的遗传靶向T细胞在调节该微环境中的作用，3）研究安全性以及开发和测试自杀基因方法以在完全肿瘤根除后选择性地删除修饰的T细胞。本提案的目的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显著抑制因子具有抗性，包括TGF 3、抑制性细胞因子TGF 2和IL-10，以及肿瘤微环境中表达的PD-L1对T细胞的PD-1活化。该提议的目的2将检验以下假设：靶向T细胞的局部IL-12分泌将募集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，从而拓宽抗肿瘤免疫库。该方案的目的3将研究IL-12分泌靶向T细胞在免疫活性宿主中的潜在副作用，并进一步测试一种新的自杀基因方法，该方法旨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的安全性。这些研究产生的数据最终将为在未来的血液系统和实体瘤恶性肿瘤患者过继免疫治疗临床试验中使用分泌IL-12的肿瘤靶向T细胞提供依据。

项目成果

Cellular therapies in acute lymphoblastic leukemia.

• DOI: 10.1016/j.hoc.2011.09.015
• 发表时间: 2011-12
• 期刊: Hematology/oncology clinics of North America
• 作者: Park JH;Sauter C;Brentjens R
• 通讯作者: Brentjens R

Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer.

• 发表时间: 2010
• 期刊: Discovery medicine
• 影响因子: 1.4
• 作者: A. Chekmasova;R. Brentjens

Chimeric Antigen Receptor Therapy for Chronic Lymphocytic Leukemia: What are the Challenges?

• DOI: 10.1016/j.hoc.2012.12.004
• 发表时间: 2013-04-01
• 期刊: HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
• 影响因子: 2.4
• 作者: Davila, Marco L.;Brentjens, Renier
• 通讯作者: Brentjens, Renier

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

• DOI: 10.1136/jitc-2021-004128
• 发表时间: 2022-03
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Palomba ML;Qualls D;Monette S;Sethi S;Dogan A;Roshal M;Senechal B;Wang X;Rivière I;Sadelain M;Brentjens RJ;Park JH;Smith EL
• 通讯作者: Smith EL

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

• 发表时间: 2010-04
• 期刊: Discovery medicine
• 影响因子: 1.4
• 作者: Jae H. Park;R. Brentjens