Marrow Infiltrating Lymphocyte Immunotherapy in Myeloma

骨髓瘤的骨髓浸润淋巴细胞免疫治疗

• 批准号: 7585123
• 负责人: Ivan M. Borrello
• 金额: $ 36.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585123
• 关键词: Adoptive Immunotherapy; Allogenic; Antigens; Autologous; Autologous Stem Cell Transplantation; Autologous Transplantation; Blood; Bone Marrow; CXCR4 gene; Candida; Cells; Clinical; Clinical Research; Clinical Trials; Condition; Data; Dendritic Cells; Development; Diagnosis; Disease; Disease Progression; Disease remission; Donor Lymphocyte Infusion; Event; Graft vs Tumor Effect; Immune; Immune response; Immunity; Immunotherapy; In Vitro; In complete remission; Kinetics; Long-Term Survivors; Lymphocyte; Lymphopenia; Malignant - descriptor; Marrow; Measurable; Mediating; Memory; Modeling; Monoclonal Antibody HuM291; Multiple Myeloma; Mumps; Muromonab-CD3; Mus; Numbers; Patients; Peripheral Blood Lymphocyte; Peripheral Stem Cell Transplant; Phase; Plasma Cells; Pneumococcal vaccine; Prevnar; Public Health; Publishing; Rate; Relapse; Residual Neoplasm; Specificity; Standards of Weights and Measures; Stem cell transplant; Surface; T memory cell; T-Lymphocyte; Therapeutic; Time; Toxic effect; Transplant Recipients; Transplantation; Vaccine Therapy; Vaccines; cell killing; chemotherapy; clinical efficacy; improved; killings; neoplastic cell; novel; novel strategies; peripheral blood; reconstitution; research study; response; trafficking; tumor

DESCRIPTION (provided by applicant): Multiple myeloma is currently incurable with available treatments. While autologous transplants have been demonstrated to delay disease progression, all patients will ultimately relapse with disease. In contrast, allogeneic transplants have increased the number of patients achieving a complete remission that may result in long-term cures suggestive of a measurable immune-mediated anti-tumor effect. Broader applicability is, however, limited by donor availability and excessive toxicity. To date, we have conducted a vaccine study as well as a trial utilizing autologous peripheral blood lymphocytes (PBLs) activated in vitro with anti-CD3/CD28 beads. The lack of functional effector T cells in the former and the absence of tumor-specificity in the latter studies significantly limited the overall anti-tumor specificity. Marrow infiltrating lymphocytes (MILs) represent a novel approach to isolate and expand T cells from the bone marrow microenvironment in patients with hematologic disorders and they demonstrate greater tumor specificity than is observed with PBLs. These cells recognize and kill myeloma cells more effectively than PBLs. Furthermore, they express surface markers such as CXCR4 thereby increasing their likelihood of trafficking to the marrow upon reinfusion and they possess fewer regulatory T cells than their PBL counterparts. In addition to killing mature, malignant plasma cells, they also recognize the myeloma precursors thereby offering the possibility of inducing long-lasting clinical responses. Lastly, in NOD/SCID experiments we see evidence of trafficking and long-term persistence of MILs in the bone marrow of mice with an associated potent anti-tumor effect. We, thus, propose a clinical study to examine the anti-myeloma efficacy of activated MILs infused following an autologous transplant. The kinetics of immune reconstitution, tumor-specific T cell activity against mature plasma cells in both the peripheral blood as well as marrow will be examined in addition to the parameters of clinical responsiveness. PUBLIC HEALTH RELEVANCE: Multiple myeloma is currently incurable with autologous stem cell transplants which have been used with certain clinical efficacy but are not curative. Immunotherapy can increase the anti-myeloma efficacy of transplants and we have recently shown that bone marrow derived T cells "immune cells" have potent anti-myeloma activity. We will perform a clinical trial utilizing these activated marrow infiltrating lymphocytes in myeloma patients.

描述（由申请人提供）：多发性骨髓瘤目前无法治愈。尽管已证明自体移植会延迟疾病的进展，但所有患者最终都会因疾病复发。相反，同种异体移植增加了达到完全缓解的患者数量，这可能会导致长期治愈的治疗方法，以表明可测量的免疫介导的抗肿瘤作用。但是，更广泛的适用性受供体的可用性和过度毒性的限制。迄今为止，我们已经进行了一项疫苗研究以及一项使用抗CD3/CD28珠在体外激活的自体外周血淋巴细胞（PBLS）的试验。在前者中缺乏功能效应T细胞，而后者的研究中缺乏肿瘤特异性，显着限制了总体抗肿瘤特异性。骨髓浸润淋巴细胞（MILS）代表了一种新型方法，可在血液学疾病患者的骨髓微环境中分离和扩展T细胞，并且与PBL相比，它们表现出更大的肿瘤特异性。这些细胞比PBL更有效地识别和杀死骨髓瘤细胞。此外，它们表达了表面标记，例如CXCR4，从而增加了将其贩运到骨髓后的可能性，而调节T细胞的调节性T细胞比PBL对应物少。除了杀死成熟的恶性血浆细胞外，它们还识别骨髓瘤前体，从而提供诱导持久临床反应的可能性。最后，在点头/SCID实验中，我们看到了小鼠骨髓中贩运和长期持久性的证据，并具有相关的有效抗肿瘤作用。因此，我们提出了一项临床研究，以检查自体移植后注入活性的MILS的抗肿瘤瘤疗效。除临床反应能力的参数外，还将检查免疫重建，肿瘤特异性T细胞对成熟浆细胞的T细胞活性。公共卫生相关性：当前多发性骨髓瘤与已使用具有某些临床功效但无法治愈的自体干细胞移植物无法治愈。免疫疗法可以提高移植的抗肿瘤瘤疗效，我们最近表明，骨髓衍生的T细胞“免疫细胞”具有有效的抗肌瘤活性。我们将使用这些激活的骨髓浸润淋巴细胞进行临床试验。