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: 8535698
• 负责人: Eduardo V Davila
• 金额: $ 30.57万
• 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/8535698
• 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.

描述（由申请人提供）：尽管进行了高剂量的化疗和自体干细胞移植（ASCT）和靶向疗法，但骨髓瘤仍然无法治愈。回顾性研究表明，在移植后早期，更好的临床结局可能与更快的淋巴细胞恢复有关。此外，肿瘤反应性T细胞在骨髓中的低频或骨髓瘤患者的血液中存在。因此，增加移植后自体T细胞的恢复和功能的策略在临床上可能是有益的。此外，它们有可能与当前的疗法协同作用，以促进缓解并实现长期无疾病的生存。我们已经对多发性骨髓瘤进行了几项过养T细胞疗法的试验，检验了以下假设，即通过静脉注入EX-VIVO CD28综合的T细胞改善T细胞恢复可能会为移植后免疫疗法提供平台，并增强疫苗策略。在促进中央记忆细胞和TH1/TC1功能的条件下，人造抗原呈现细胞刺激自体T细胞。 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.在第二项研究中，该组合疫苗和T细胞免疫疗法的平台还以相当一部分患者的比例与假定的肿瘤抗原疫苗相对于由人端粒酶（HTERT）和survivin组成的假定肿瘤抗原疫苗。当前，我们正在研究使用基于MAGE-A3的不同疫苗和一种称为Poly-ICLC（TLR-3受体激动剂）的新型疫苗佐剂，可以通过使用不同的疫苗来增强骨髓瘤指导的免疫反应的频率和大小。但是，到目前为止，我们至少有两个潜在的方法：i）i）收养的T细胞是多克隆的，因此只有很小的比例才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/扩展之前的自体T细胞的成功“启动”，这一过程效率低下，尤其是在主动恶性肿瘤的情况下。为了解决该提案中有效免疫疗法的这些障碍，我们将通过转导慢病毒构建体来修饰自体T细胞，这些齿病毒构建体编码了两个自然处理的表位，这些植物构造了tumor抗原抗原Mage-A3和Nyy-Eso-1。这些癌症/睾丸肿瘤抗原（CTAG）经常在骨髓瘤细胞中表达。我们将特别研究自体干细胞移植（ASCT）后是否可以安全转移这些转导细胞，以及这些基因修饰的T细胞是否持续存在，功能和靶向患者的骨髓瘤细胞。我们还将使用Lenalidomide作为骨髓瘤和可能的免疫调节剂的移植后维持治疗。最近的工作表明，Lenalidomide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细胞是安全且功能性的，那么ASCT的这种组合策略随后是“重定向”的自体T细胞的继发性转移可能是有效移植后移植物免疫疗法以及其他血液学肿瘤的平台。