Optimizing the Graft-Versus-Tumor Effect in Allogeneic HSCT

优化同种异体 HSCT 中的移植物抗肿瘤效应

• 批准号: 8158297
• 负责人: michael r bishop
• 金额: $ 32.08万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 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/8158297
• 关键词: AML/MDS; Address; Aliquot; Allogenic; CCR; Correlative Study; Disease; Donor Lymphocyte Infusion; Graft-Versus-Tumor Induction; Stem cell transplant; Strategic Planning; prevent

Background: A significant component of the therapeutic effect of allogeneic hematopoietic stem cell transplantation (alloHSCT) is mediated by lymphocytes, particularly T cells, in the allograft (i.e. graft-versus-tumor [GVT] effect). However, the degree to which GVT effect contributes to the efficacy of alloHSCT differs significantly between various malignancies. In patients with extremely chemotherapy-refractory tumors and/or tumors with rapid growth kinetics, the GVT effect may be insufficiently potent to be detectable because the tumor had developed resistant mechanism which inhibit or are lss susceptible to to GVT effects or the tumor growth rate exceeds the ability of the immune effect to eliminate disease. The susceptibility of various malignancies to the GVT effect most likely reflects the biologic characteristics that are unique to that respective disease, such as growth rate and antigen expression. Due to this significant heterogeneity, we initially elected to focus our research efforts, relative to GVT effects, on a single disease group, B cell malignancies. More recent efforts have been focused on pre-clinical studies in myeloid malignancies. NCI Strategic Plan Relevance: Develop Effective and Efficient Treatments Project Goals: 1. Develop novel treatment strategies for patients with persistent or recurrent disease after allogeneic adoptive cellular therapy The management and treatment of relapse or progression of disease following alloHSCT is a significant clinical problem. Treatment options are extremely limited for patients who experience disease recurrence or progression following alloHSCT. These options include the withdrawal of immune suppression and/or the administration of donor lymphocyte infusions (DLI), the use of conventional therapeutic treatments for the respective disease, or a second alloHSCT. With the exception of chronic phase chronic myelogenous leukemia, these treatments only benefit a minority of patients, the benefits are often transient, and the treatments are associated with a high degree of morbidity, particularly GVHD. In addition, many of these therapies are not applicable to patients in whom disease recurs while experiencing active GVHD. After alloHSCT, lymphocytes are found infiltrating residual tumor. It is likely that these cells are of donor origin and may exhibit enhanced antigen specificity and tumor-specific homing. Compared to donor peripheral blood lymphocytes or to tumor-infiltrating lymphocytes in non-transplant patients, the lymphocytes found in tumor after alloHSCT may have a higher potential for disease control. It was our hypothesis that lymphocytes found in tumor after alloHSCT are of donor origin, and because they are tumor-derived, they may be tumor-specific in their homing and antigen specificity characteristics. Further, activation and expansion of these cells through CD3/CD28 costimulation may yield a more effective form of cell therapy after alloHSCT, with enhanced GVT effects and less GVHD. Pre-clinical studies of the costimulation technique were evaluated using autologous lymphocytes derived from a variety of tumor types (i.e. from anonymous patients having tumor resected for clinical indications). A two-week culture with CD3/CD28 costimulation resulted in up to 30-fold increase in T cell numbers. Several important observations were made during these pre-clinical studies. The first was the addition of tumor to the culture resulted in 3- to 10-fold better yield of T cells as compared to cultures without tumor cells, suggesting the possibility of antigen-driven expansion. Second, an additional round of cell costimulation yielded additional 10-fold expansion. Third, in cultures containing tumor cells, tumor cell death was observed, suggesting either T-cell mediated killing and/or the culture conditions were not conducive to tumor cell growth. Fourth, costimulation and culture yielded a cell production with an effector memory cell phenotype and minimal numbers of cells with a T-regulatory phenotype. Based on these pre-clinical data, a protocol, 07-C-0064, for the clinical use of allogeneic TDL for treatment of B-cell malignancies which have relapsed after alloHSCT was written and and subsequently received FDA IND approval in January 2007. The primary objective of the study is to evaluate the feasibility of administering ex-vivo costimulated/expanded TDL in patients with persistent or recurrent BCL following alloHSCT. Specific feasibility aims include the consistent isolation, costimulation and expansion of clinically relevant numbers of TDL from resected tumor specimens. The other primary aim is to determine the safety of administering TDL relative to infusion toxicities and hyperacute GVHD. The protocol has a number of correlative studies which include both tumor and lymphocyte characterization prior to culture and characterization of the immune phenotypic and functional characteristics of TDL after culture. In addition attempts will be made at target antigen discovery, through SEREX-related methods for the identification of tumor-reactive donor T cell targets. Nine patients have been enrolled onto this this clinical trial. We have have been able to demonstate teh feasibility and safety of this approach. there have been two objective responses. We have broadened the application of thsi approach to utilize bone marrow with tumor invovlement. Similar to pre-clinical results with lymph nodes we were able to demonstrate that clinical grade and number T lymphocytes, free of relevant tumor contamination could be generated from small (10-20 ml) aliquots. Based on these results with B-lymphoid malignancies, we have recently completed pre-clinical studies using bone marrow samples from patients with myeloid malignancies (AML and MDS). These studies demonstrated that lymphocytes with effector phenotypes could be generated to clinically significant numbers fro of leukemic contamination from small marrow aliquots. Currently an application for an IND is in preparation with subsequent plans to implement two clinical protocols for relapsed AML/MDS in the pre- and post-transplant settings, respectively. 2. Develop a trans-NIH multidisciplinary clinical research program addressing the problem of disease relapse after allogeneic stem cell transplantation. In major collaboration with POB (A Wayne, T Fry) we have initiated a major effort to study the biology, natural history, and to treat relapsed hematologic malignancies after allogeneic stem cell transplantation. these efforts include the establishment of a relapse working group (Bishop, Wayne and Hardy) which meets regularly to coordinate all of these efforts. There is a monthly relapse tumor board which bring together investigators from multiple disciplines (e.g. pathology, radiology, radiation oncology, medical oncology, etc..) from within CCR and across NIH (NHLBI, CC). A formal relapse clinic has been established which utilizes all CCR protocols for which patients with relapsed disease after allogeneic HSCT aare eligible. A Natural history protocol, which studies tumor biology and patient characteristics has been written and it is anticipated that it will be submitted to the IRB before the end of 2010.

背景：同种异体造血干细胞移植（AllOHSCT）的治疗作用的重要组成部分是由同种异体移植物中的淋巴细胞，尤其是T细胞介导的（即移植物 - 肿瘤[GVT]效应）。但是，GVT效应在各种恶性肿瘤之间有助于AllOHSCT的功效有很大差异。在患有极端化学疗法 - 难治性肿瘤和/或具有快速生长动力学的肿瘤的患者中，GVT效应可能不足以检测到无法检测到的，因为该肿瘤已经开发出耐药机制，该耐药机制抑制或容易患有GVT的LSS或肿瘤生长效应超过免疫效应的能力，无法消除疾病。各种恶性肿瘤对GVT效应的敏感性很可能反映出各自疾病所特有的生物学特征，例如生长速率和抗原表达。由于这种重要的异质性，我们最初选择将研究工作集中在单个疾病组B细胞恶性肿瘤上。最近的努力集中在髓样恶性肿瘤的临床前研究上。 NCI战略计划相关性：制定有效有效的治疗项目项目目标：1。在同种异体产卵性细胞疗法后，为患有持续或复发性疾病的患者制定新的治疗策略。在AllOHSCT后，疾病复发或进展的治疗是一个重大的临床问题。对于经历疾病复发或进展后，治疗方案极为有限。这些选择包括戒除免疫抑制和/或给予供体淋巴细胞输注（DLI），用于各自疾病的常规治疗治疗或第二个AllOHSCT。除了慢性慢性骨髓性白血病外，这些治疗只会使少数患者受益，益处通常是短暂的，并且治疗与高度的发病率相关，尤其是GVHD。此外，这些疗法中的许多不适用于在经历活跃GVHD时复发的患者。 在AlloHSCT之后，发现淋巴细胞浸润残留肿瘤。这些细胞可能是供体起源，并且可能表现出增强的抗原特异性和肿瘤特异性归巢。与非移植患者的供体外周血淋巴细胞或肿瘤淋巴细胞相比，在AllOHSCT后在肿瘤中发现的淋巴细胞可能具有更高的疾病控制潜力。我们的假设是，在AllOHSCT之后在肿瘤中发现的淋巴细胞是供体的起源，并且由于它们是肿瘤衍生的，因此它们的归因和抗原特异性特异性可能是肿瘤特异性的。此外，这些细胞通过CD3/CD28共刺激对这些细胞的激活和扩展可能会在AllOHSCT后产生更有效的细胞疗法形式，具有增强的GVT效应，GVHD较少。 使用源自各种肿瘤类型的自体淋巴细胞评估了共刺激技术的临床前研究（即，从匿名患者中切除肿瘤的临床适应症）。用CD3/CD28共刺激为期两周的培养，T细胞数量最大增加了30倍。在这些临床前研究期间，进行了一些重要的观察。首先是与没有肿瘤细胞的培养物相比，在培养物中添加肿瘤，​​导致T细胞的产量优于3至10倍，这表明抗原驱动的扩张的可能性。其次，另外一轮细胞共刺激产生了额外的10倍膨胀。第三，在含有肿瘤细胞的培养物中，观察到肿瘤细胞死亡，这表明T细胞介导的杀伤和/或培养条件不利于肿瘤细胞生长。第四，共刺激和培养产生了具有效应记忆细胞表型的细胞产生，具有T调节表型的细胞数量最少。 Based on these pre-clinical data, a protocol, 07-C-0064, for the clinical use of allogeneic TDL for treatment of B-cell malignancies which have relapsed after alloHSCT was written and and subsequently received FDA IND approval in January 2007. The primary objective of the study is to evaluate the feasibility of administering ex-vivo costimulated/expanded TDL in patients with persistent or recurrent BCL following allohsct。具体的可行性目的包括从切除的肿瘤标本中持续的隔离，共刺激和临床相关数量的TDL的扩展。另一个主要目的是确定施用TDL相对于输注毒性和超急性GVHD的安全性。该方案有许多相关研究，包括培养和培养物的培养和特征表征肿瘤和淋巴细胞表征，培养后TDL的免疫表型和功能特征。此外，将通过与SEREX相关的方法鉴定肿瘤反应性供体T细胞靶标，在目标抗原发现中进行尝试。这项临床试验已招募了9名患者。我们已经能够解决这种方法的可行性和安全性。有两个客观回应。我们扩大了THSI方法利用肿瘤的骨髓的应用。与淋巴结的临床前结果相似，我们能够证明，临床等级和数量T淋巴细胞，没有相关肿瘤污染，可以从小（10-20 mL）等分试样产生。基于B-淋巴恶性肿瘤的这些结果，我们最近使用髓样恶性肿瘤患者（AML和MDS）的骨髓样品完成了临床前研究。这些研究表明，具有效应表型的淋巴细胞可以从小骨髓等分试样从白血病污染中产生临床意义。目前，IND的申请正在准备随后的计划，计划分别在移植前和移植后设置中实施两个临床方案。 2。开发一项跨性别学科的临床研究计划，以解决同种异体干细胞移植后疾病复发问题。 在与POB（A Wayne，T Fry）的主要合作中，我们开始了一项重大努力，以研究生物学，自然史，并在同种异体干细胞移植后治疗复发的血液学恶性肿瘤。这些努力包括建立一个复发工作组（Bishop，Wayne和Hardy），定期开会以协调所有这些努力。有一个每月的复发肿瘤板，将来自CCR内部和NIH（NHLBI，CC）的多个学科（例如病理学，放射学，放射肿瘤学，医学肿瘤学等）的研究人员聚集在一起。已经建立了一个正式的复发诊所，该诊所利用了所有CCR方案，在同种异体HSCT AARE符合条件后，患有复发性疾病的患者。一项研究肿瘤生物学和患者特征的自然历史方案已经编写，预计将在2010年底之前提交给IRB。