Adoptive transfer of gene-modified autologous T-cells post-ASCT for myeloma

ASCT 后过继转移基因修饰的自体 T 细胞治疗骨髓瘤

• 批准号: 8396738
• 负责人: MICHAEL D KALOS
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396738
• 关键词: Address; Adoptive Transfer; Affinity; Agonist; Allogenic; Animal Model; Antigen Targeting; Antigen-Presenting Cells; Antigens; Area; Autoantigens; Autologous; Autologous Stem Cell Transplantation; B-Lymphocytes; Blood; CD28 gene; CD4 Positive T Lymphocytes; CTAG1 gene; Cancer Vaccines; Cell Count; Cells; Clinical; Clinical Trials; Collection; Combined Vaccines; Development; Disease; Disease remission; Disease-Free Survival; Donor person; Dose; Epitopes; Exhibits; Frequencies; Gene Transfer; Gene-Modified; Genes; Goals; Graft vs Tumor Effect; Hematologic Neoplasms; High Dose Chemotherapy; Human; Immune; Immune Tolerance; Immune response; Immunomodulators; Immunotherapy; Infusion procedures; Intravenous infusion procedures; Lymphocyte; Maintenance; Malignant Neoplasms; Marrow; Measures; Mediating; Memory; Methods; Minority; Multiple Myeloma; Outcome; Patients; Peptide Vaccines; Peptides; Phase; Pneumococcal 7-Valent Conjugate Vaccine; Poly ICLC; Process; Property; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Relapse; Retrospective Studies; Safety; Secondary Immunization; Specificity; Stem cell transplant; T cell therapy; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Technology; Telomerase; Testicular Neoplasms; Testing; Th1 Cells; Toxic effect; Transplantation; Tumor Antigens; Tumor Cell Derivative Vaccine; Tumor Immunity; Vaccine Adjuvant; Vaccines; Work; base; cellular engineering; cellular transduction; clinically significant; cohort; design; graft vs host disease; immunogenicity; improved; in vivo; lenalidomide; mortality; neoplastic cell; novel vaccines; receptor; response; selective expression; survivin; trafficking; tumor

DESCRIPTION (provided by applicant): Myeloma remains largely incurable in spite of high-dose chemotherapy and autologous stem cell transplantation (ASCT) and targeted therapies. Retrospective studies suggest that better clinical outcomes may be associated with more rapid lymphocyte recovery during the early post-transplant period. In addition, tumor-reactive T-cells are present at low frequencies in the marrow or blood of untreated patients with myeloma. Thus, strategies to augment the recovery and function of autologous T-cells post-transplant may be clinically beneficial. Furthermore, they have the potential to synergize with current therapies to promote remissions and achieve long term disease free survival. We have conducted several trials of adoptive transfer T cell therapy for multiple myeloma, testing the hypothesis that improved T-cell recovery through intravenous infusion of ex-vivo CD28 costimulated T cells might provide a platform for post-transplant immunotherapy and enhance vaccine strategies. Autologous T-cells were stimulated by artificial antigen presenting cells under conditions that promote central memory cells and Th1/Tc1 function. In the first study, a 7-valent pneumococcal conjugate vaccine (PCV) was used as a well-defined antigen which allowed us to show that the adoptive transfer of in-vivo vaccine-primed and ex-vivo costimulated autologous T-cells early after transplant led to enhanced T-cell recovery and generated vaccine-specific T and B-cell responses. In the second study, this platform of combined vaccine and T-cell immunotherapy also generated immune responses in a significant proportion of patients against a putative tumor antigen vaccine composed of peptides derived from human telomerase (hTERT) and survivin. Currently, we are studying whether the frequency and magnitude of the myeloma-directed immune responses can be enhanced by using a different vaccine based on MAGE-A3 and a novel vaccine adjuvant called Poly-ICLC (a TLR-3 receptor agonist). However, there are at least two potential drawbacks of the approach that we have taken so far: i) the adoptively transferred T-cells are polyclonal and thus only a small proportion are truly directed against the myeloma tumor cells; and ii) the myeloma specificity depends on successful "priming" of the autologous T-cells prior to collection and costimulation/expansion, a process that is inefficient especially in the setting of active malignancy. To address these impediments to effective immunotherapy in this proposal, we will genetically modify autologous T-cells through transduction of lentiviral constructs which encode high-affinity T-cell receptors (TCRs) for two naturally processed epitopes that are derived from tumor antigens MAGE-A3 and NY-ESO-1. These cancer/testis tumor antigens (CTAgs) are frequently and specifically expressed in myeloma cells. We will specifically study whether these transduced cells can be safely transferred very soon after autologous stem cell transplantation (ASCT) and whether these gene-modified T-cells persist, function and target myeloma cells in patients. We will also use lenalidomide both as a post-transplant maintenance treatment for myeloma and as a possible immunomodulator. Recent work indicates that lenalidomide may have important immunostimulatory properties. If this study shows that TCR-gene modified T-cells are safe and functional then this combination strategy of ASCT followed by adoptive transfer of "redirected" autologous T-cells could be a platform for effective post-transplant immunotherapy of myeloma and perhaps other hematologic neoplasms. PUBLIC HEALTH RELEVANCE: Our long-term goal is to develop a strategy for generating clinically effective immune responses against myeloma in order to potentially increase the likelihood of long-term remission and cure. Our hypothesis is that adoptive transfer of expanded/activated autologous T cells that are genetically "redirected" toward myeloma tumor targets will be safe and may result in significant anti-tumor immunity after autologous stem cell transplantation for myeloma. The current proposal is based on our fourth major clinical trial in the area of post-transplant adoptive T-cell therapy.

描述（由申请人提供）：尽管进行了大剂量化疗、自体干细胞移植（ASCT）和靶向治疗，骨髓瘤在很大程度上仍然无法治愈。回顾性研究表明，更好的临床结果可能与移植后早期更快的淋巴细胞恢复有关。此外，肿瘤反应性t细胞在未经治疗的骨髓瘤患者的骨髓或血液中也以低频率存在。因此，增强移植后自体t细胞的恢复和功能的策略可能在临床上是有益的。此外，它们有可能与目前的疗法协同作用，以促进缓解并实现长期无病生存。我们已经对多发性骨髓瘤的过继性转移T细胞治疗进行了几项试验，验证了通过静脉输注离体CD28共刺激T细胞改善T细胞恢复的假设，这可能为移植后免疫治疗和增强疫苗策略提供一个平台。在促进中枢记忆细胞和Th1/Tc1功能的条件下，人工抗原提呈细胞刺激自体t细胞。在第一项研究中，一种7价肺炎球菌结合疫苗（PCV）被用作一种定义明确的抗原，这使我们能够证明，移植后早期体内疫苗引发和体外共刺激的自体T细胞的过继转移可以增强T细胞的恢复，并产生疫苗特异性的T细胞和b细胞反应。在第二项研究中，这种联合疫苗和t细胞免疫治疗的平台也在很大比例的患者中产生了免疫应答，以对抗推定的肿瘤抗原疫苗，该疫苗由人类端粒酶（hTERT）和生存素衍生的肽组成。目前，我们正在研究是否可以通过使用基于MAGE-A3的不同疫苗和一种称为Poly-ICLC（一种TLR-3受体激动剂）的新型疫苗佐剂来增强骨髓瘤定向免疫反应的频率和强度。然而，到目前为止，我们所采用的方法至少有两个潜在的缺点：i)过过性转移的t细胞是多克隆的，因此只有一小部分真正针对骨髓瘤肿瘤细胞；ii)骨髓瘤特异性取决于在收集和共刺激/扩增之前成功“启动”自体t细胞，这一过程效率低下，特别是在活动性恶性肿瘤的情况下。为了解决这些阻碍有效免疫治疗的障碍，我们将通过慢病毒构建体的转导对自体t细胞进行遗传修饰，该慢病毒构建体编码高亲和力t细胞受体（tcr），用于两个天然加工的表位，这两个表位来源于肿瘤抗原MAGE-A3和NY-ESO-1。这些癌/睾丸肿瘤抗原（CTAgs）经常在骨髓瘤细胞中特异性表达。我们将专门研究这些转导的细胞能否在自体干细胞移植（ASCT）后很快安全地转移，以及这些基因修饰的t细胞能否在患者体内持续存在、发挥功能并靶向骨髓瘤细胞。我们还将使用来那度胺作为骨髓瘤移植后的维持治疗和可能的免疫调节剂。最近的研究表明来那度胺可能具有重要的免疫刺激特性。如果这项研究表明tcr基因修饰的t细胞是安全和功能性的，那么ASCT的联合策略以及“重定向”自体t细胞的过继转移可能成为骨髓瘤和其他血液学肿瘤移植后有效免疫治疗的平台。