Cellular Immunotherapy for Follicular Lymphoma Using CD19- Specific T-Cells

使用 CD19 特异性 T 细胞治疗滤泡性淋巴瘤的细胞免疫疗法

• 批准号: 7682152
• 负责人: Michael C Jensen
• 金额: $ 10.41万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7682152
• 关键词: 90Y; Ablation; Accounting; Adoptive Immunotherapy; Adoptive Transfer; Age-Years; Algorithms; Alkylating Agents; Allogeneic Bone Marrow Transplantation; Allogenic; American; Amino Acids; Animal Model; Animals; Antibodies; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autologous; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding Sites; Biology; Bispecific Antibodies; Blood; Blood Circulation; Body Surface; Bone Marrow; Bos taurus; Bulky Disease; CD19 gene; CD28 gene; CD3 Antigens; CD8B1 gene; Cancer Patient; Cattle; Cell Death; Cell Line; Cell Separation; Cell surface; Cells; Cessation of life; Chimeric Proteins; Cities; Clinical; Clinical Research; Clinical Trials; Cloning; Complementary DNA; Complex; Complication; Computer software; Cytolysis; Cytomegalovirus; Cytoplasmic Tail; Data; Development; Diagnosis; Disease; Disease regression; Donor Lymphocyte Infusion; Dose; Effector Cell; Employee Strikes; Engineering; Epitopes; Evaluation; Extracellular Domain; Facility Construction Funding Category; Follicular Lymphoma; Ganciclovir; Generations; Genes; Genetic; Graft-Versus-Tumor Induction; HIV; Hematopoietic Stem Cell Transplantation; Homing; Hour; Human; Human Herpesvirus 4; Hybridomas; ITAM; IgG4; Image; Immune; Immune response; Immunity; Immunobiology; Immunocompetent; Immunoglobulin Variable Region; Immunoglobulins; Immunologic Surveillance; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Incidence; Individual; Indolent; Influenza; Infusion procedures; Injection of therapeutic agent; Interferon Type II; Isoflurane; K-562; Left; Life; Ligands; Light; Lighting; Localized; Luciferases; Lymphocyte; Lymphoid Tissue; Lymphokine-Activated Killer Cells; Lymphoma; Lymphoproliferative Disorders; MS4A1 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Methodology; Modality; Modification; Molecular Conformation; Monoclonal Antibodies; Monoclonal Antibody HuM291; Monophenol Monooxygenase; Morbidity - disease rate; Muromonab-CD3; Mus; Non-Hodgkin' s Lymphoma; Numbers; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Photons; Pilot Projects; Poly A; Population; Population Heterogeneity; Positioning Attribute; Principal Investigator; Progressive Disease; Proliferating; Proteins; Protocols documentation; Purpose; Radiation therapy; Radioconjugate; Radioimmunotherapy; Range; Rate; Receptor Signaling; Recruitment Activity; Recurrence; Recycling; Refractory; Refractory Disease; Relapse; Reproduction spores; Residual Neoplasm; Resistance; Risk; Safety; Signal Pathway; Signal Transduction; Simian virus 40; Site; Solutions; Somatotropin; Source; Specificity; Specimen; Staging; Stem cell transplant; Structure; Structure of germinal center of lymph node; Suicide; System; T-Cell Activation; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Tail; Technology; Therapeutic; Therapeutic Intervention; Thymidine Kinase; Time; Tissues; Titrations; Toxic effect; Transgenes; Translating; Transmembrane Domain; Transplantation; Treatment Failure; Treatment Protocols; Tumor Antigens; Tumor Escape; Tumor Immunity; Vaccination; Vaccines; Veins; Viral; Viral Antigens; Western Blotting; anergy; antigen binding; aqueous; base; cancer cell; cell killing; cell type; cellular engineering; charge coupled device camera; chemotherapy; clinical application; clinical efficacy; concept; crosslink; cytokine; day; design; desire; digital imaging; experience; expression cloning; extracellular; fludarabine; gene therapy; graft vs host disease; hygromycin A; hygromycin-B kinase; immunogenicity; implantation; improved; in vivo; insight; leukemia/lymphoma; light intensity; luciferin; lymph nodes; melanoma; neoplastic; neoplastic cell; novel; older patient; plasmid DNA; pre-clinical; preclinical study; prevent; programs; promoter; prototype; purine analog; receptor; reconstitution; response; retroviral transduction; rituximab; selective expression; subcutaneous; suicide gene; tositumomab; transgene expression; tumor; tumor eradication

Currently available therapeutics for follicular lymphoma (FL) have limited curative potential and significant toxicities, particularly for the older FL patient population. Novel treatment modalities, such as immunotherapy, that can combine enhanced anti-tumor efficacy with diminished toxicities through targeting of malignant B-cells of FL are needed. The studies proposed here will build on the advances made in FL immunotherapy through antibody-based therapeutics by developing complimentary cellular immunotherapy-based approaches for this disease. We have made significant progress in developing the methodologies for isolating and expanding genetically-modified T-cells that express a CD19-specific chimeric immunoreceptor and display potent and specific anti-tumor effector functioning against CD19 + lymphomas. Moreover, the City of Hope has established platforms for manufacturing clinical-grade genetically-modified ex vivo-expanded T-cell products under FDA-authorized IND's. A pilot Phase I clinical trial is proposed to treat, for the first time, FL patients with refractory/progressive disease with autologous ex vivo-expanded CD19-specific T-cell lines (Aim 1). In addition to answering questions of feasibility, safety, and anti-tumor responses, this trial will study the in vivo persistence, lymph node homing, and immunogenicity of these cell products. The magnitude and duration of in vivo persistence of adoptivelytransferred CD19-specific T-cells will likely be important parameters for clinical efficacy. While we will study the impact of pre-adoptive therapy lymphodepletion and exogenous IL-2 administration on promoting persistence in the context of our pilot study, Aim 2 of this proposal will focus on pre-clinical development of strategies to selectively express the anti-CD19 immunoreceptor in T-cells having desired anti-viral specificity through their endogenous TCRs. Ultimately we hypothesize that such bi-specific T-cells will be amenable to in vivo expansion through vaccination with viral antigen. Aim 3 will focus on promoting the survival and recycling of CD19-specific T-cells in the lymphoma microenvironment by their co-expression of CD28 for coordinated delivery of activation and co-stimulation signals by tumor cells of FL. We anticipate that insights gained from the pilot clinical trial and proposed pre-clinical studies will facilitate the implementation of second-generation adoptive immunotherapy protocols for FL with applications to other B-lineage lymphomas

目前可用于卵泡淋巴瘤（FL）的治疗剂具有有限的治疗潜力和显着的毒性，特别是对于老年佛罗里达患者人群。需要通过靶向FL的恶性B细胞来结合增强的抗肿瘤功效与毒性降低的新型治疗方式，例如免疫疗法。此处提出的研究将基于通过基于抗体的治疗剂在FL免疫疗法中取得的进步，通过开发基于该疾病的免费细胞免疫疗法方法。我们在开发了隔离和扩展遗传改性的T细胞的方法方面取得了重大进展，这些T细胞表达CD19特异性嵌合免疫受体，并显示出针对CD19 +淋巴瘤的有效和特定的抗肿瘤效应功能。此外，希望之城已经建立了在FDA授权的IND下制造临床级遗传改性的T-T细胞产品的平台。提出了一项I阶段临床试验，该试验首次治疗患有自体外膨胀CD19特异性T细胞系的FL患者（AIM 1）。除了回答有关可行性，安全性和抗肿瘤反应的问题外，该试验还将研究这些细胞产物的体内持久性，淋巴结归位和免疫原性。在临床功效中，采用转移的CD19特异性T细胞的体内持久性的大小和持续时间可能是重要的参数。虽然我们将研究辅助治疗前淋巴结消退和外源性IL-2给药对促进持续性的影响，但该提案的目标2将重点介绍策略前的策略，以选择性地表达抗CD19的抗CD19免疫受体，在具有期望的抗Viral特异性特异性抗Virel特异性的T-Cells中 通过它们的内源性TCR。最终，我们假设这样的双特异性T细胞可以通过使用病毒抗原疫苗接种体内扩张。 AIM 3将专注于通过CD28的共表达CD19特异性T细胞在淋巴瘤微环境中的存活和回收利用，以协调FL肿瘤细胞的激活和共刺激信号。我们预计从试点临床试验中获得的见解和拟议的临床前研究将有助于对FL的第二代收养免疫疗法协议实施，并适用于其他B-Linege淋巴瘤