Marrow Infiltrating Lymphocyte Immunotherapy in Myeloma

描述（由申请人提供）：多发性骨髓瘤目前是无法治愈的。虽然自体移植已被证明可以延缓疾病进展，但所有患者最终都会复发。相反，同种异体移植增加了完全缓解的患者数量，这可能导致长期治愈，这表明免疫介导的抗肿瘤作用是可测量的。然而，更广泛的适用性受到供体供应和过度毒性的限制。到目前为止，我们已经进行了一项疫苗研究以及一项利用体外抗cd3 /CD28微球激活的自体外周血淋巴细胞（PBLs）的试验。前者缺乏功能性效应T细胞，后者缺乏肿瘤特异性，显著限制了整体抗肿瘤特异性。骨髓浸润淋巴细胞（mil）代表了一种从血液疾病患者骨髓微环境中分离和扩增T细胞的新方法，它们比pbl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，它们表达表面标记物，如CXCR4，从而增加了它们在回输时转运到骨髓的可能性，并且它们比PBL具有更少的调节性T细胞。除了杀死成熟的恶性浆细胞外，它们还能识别骨髓瘤前体，从而提供了诱导长期临床反应的可能性。最后，在NOD/SCID实验中，我们发现了mil在小鼠骨髓中运输和长期存在的证据，并具有相关的强效抗肿瘤作用。因此，我们建议进行一项临床研究，以检验自体移植后注入活化mil的抗骨髓瘤功效。除了临床反应性参数外，还将检查免疫重建动力学，肿瘤特异性T细胞对外周血和骨髓中成熟浆细胞的活性。公共卫生相关性：目前多发性骨髓瘤是无法治愈的自体干细胞移植已经使用了一定的临床疗效，但不能治愈。免疫疗法可以提高移植的抗骨髓瘤疗效，我们最近发现骨髓来源的T细胞“免疫细胞”具有强大的抗骨髓瘤活性。我们将在骨髓瘤患者中使用这些活化的骨髓浸润淋巴细胞进行临床试验。

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.