ANTIGEN SPECIFIC IMMUNITY IN MULTIPLE MYELOMA

多发性骨髓瘤中的抗原特异性免疫

基本信息

批准号：
6320828
负责人：
Lee Marshall Nadler
金额：
$ 27.53万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2001-05-31
项目状态：
已结题

项目摘要

Minimal residual disease (MRD) contaminating the stem cell source and chemo-radiotherapy resistant MRD in the multiple myeloma (MM) patient (pt) contribute to relapse following myeloablative therapy. Project 2 proposes to develop novel strategies to eradicate MRD in MM. To eradicate MRD contaminating the stem cell source, we propose to develop techniques that will purge all MM cells that can be detected by PCR. In an attempt to treat MRD within the pt, we propose to develop adoptive T cell therapy that will eradicate PCR detectable disease. To achieve these goals, we propose to undertake the basic laboratory experiments, pre-clinical studies and scale up, and clinical trials necessary to address these issues. The central hypothesis of this proposal is that human MM antigens (Ag) exist; however, due to immunosuppression in the tumor bearing host and/or ineffective Ag presentation, no clinically significant anti-MM T cell response is generated. B cell neoplasms are themselves extremely poor Ag presenting cells (APC). However, malignant B cells modified in vitro by CD40 activation become very potent APCs and can be used to ex vivo T cell stimulation of tumor-specific T cells. We have also been able to generate large numbers of normal CD40 activated B cells that can be leaded with tumor Ag and can be used ex vivo to generate autologous T cells specifically recognizing Ag on tumor cells. Preliminary evidence demonstrates that we can improve the APC capacity of MM cells to be used as stimulators for ex vivo T cell expansion. We plan to extend these observations to induce and optimize anti-MM specific T cell immunity and to translate these observation to the clinical area. We propose four Aims. First, we plan to develop technologies to purge the stem cell of contaminating MM cells and demonstrate the superiority of this product. Second, we plan to determine the T cell immunocompetence of the MM patient prior to treatment, following conventional therapy, and after myeloablative therapy. Third, we plan to develop methods to generate and expand anti-MM specific autologous T cells ex vivo and undertake clinical scale up. Finally, we plan to undertake clinical trials to adoptively transfer anti-MM specific autologous T cells to treat MRD in MM patients following myeloablative therapy. Project 2 relies upon and his highly interdependent with Project 1 (developing allogeneic MM specific immunity) and with Project 3 (vaccines to induce autologous MM specific T cell ex vivo). Critical to the success of Project 2 is Core B and C which will provide MRD detection and immune assessment.

微小残留病（MRD）污染干细胞来源和多发性骨髓瘤 (MM) 患者的放化疗耐药 MRD (pt) 有助于清髓治疗后的复发。项目2提出制定新策略来根除 MM 中的 MRD。根除MRD 污染干细胞来源，我们建议开发技术将清除所有可通过 PCR 检测到的 MM 细胞。试图治疗患者内的 MRD，我们建议开发过继性 T 细胞疗法这将消除 PCR 可检测到的疾病。为了实现这些目标，我们建议承担基础实验室实验、临床前解决这些问题所需的研究和扩大规模以及临床试验问题。该提案的中心假设是人类 MM 抗原 (Ag) 存在；然而，由于荷瘤宿主的免疫抑制和/或无效的 Ag 表现，无临床意义的抗 MM T 产生细胞反应。 B细胞肿瘤本身就非常差抗原呈递细胞 (APC)。然而，恶性 B 细胞在体外经过修饰 CD40 激活成为非常有效的 APC，可用于离体 T 细胞刺激肿瘤特异性 T 细胞。我们还能够生成大量正常 CD40 激活的 B 细胞可以用肿瘤抗原，可用于离体产生自体 T 细胞特异性识别肿瘤细胞上的Ag。初步证据表明我们可以提高所用MM细胞的APC能力作为离体 T 细胞扩增的刺激剂。我们计划扩展这些诱导和优化抗 MM 特异性 T 细胞免疫的观察结果将这些观察结果转化为临床领域。我们提出四个目标。首先，我们计划开发清除干细胞的技术污染MM细胞并证明该产品的优越性。其次，我们计划确定MM患者的T细胞免疫能力治疗前、常规治疗后和治疗后清髓治疗。第三，我们计划开发方法来生成和离体扩增抗MM特异性自体T细胞并开展临床扩大规模。最后，我们计划进行临床试验以采用转移抗MM特异性自体T细胞来治疗MM患者的MRD 清髓治疗后。项目2依赖于他的高度与项目1相互依存（开发同种异体MM特异性免疫）以及项目 3（用于诱导自体 MM 特异性 T 细胞的疫苗）体内）。项目 2 成功的关键是核心 B 和 C，它们将提供MRD检测和免疫评估。