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

描述（由申请人提供）：尽管有高剂量化疗和自体干细胞移植（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淋巴细胞恢复更快有关。此外，肿瘤反应性T细胞以低频率存在于未经治疗的骨髓瘤患者的骨髓或血液中。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有益。此外，它们具有与当前疗法协同作用的潜力，以促进缓解并实现长期无病生存。我们已经进行了几项过继转移T细胞治疗多发性骨髓瘤的试验，验证了通过静脉输注离体CD 28共刺激T细胞来改善T细胞恢复的假设，这可能为移植后免疫治疗提供一个平台，并增强疫苗策略。在促进中枢记忆细胞和Th 1/Tc 1功能的条件下，通过人工抗原呈递细胞刺激自体T细胞。在第一项研究中，7价肺炎球菌结合疫苗（PCV）被用作明确的抗原，这使我们能够证明，体内疫苗致敏和离体共刺激自体T细胞的过继转移移植后早期导致T细胞恢复增强，并产生疫苗特异性T和B细胞应答。在第二项研究中，这种联合疫苗和T细胞免疫疗法的平台也在相当大比例的患者中产生了针对由源自人端粒酶（hTERT）和存活素的肽组成的推定肿瘤抗原疫苗的免疫应答。目前，我们正在研究是否可以通过使用基于MAGE-A3的不同疫苗和称为Poly-ICLC（TLR-3受体激动剂）的新型疫苗佐剂来增强骨髓瘤导向免疫反应的频率和幅度。i）过继转移的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;和ii）骨髓瘤特异性取决于在收集和共刺激/扩增之前自体T细胞的成功“引发”，特别是在恶性肿瘤活动的情况下效率低下的过程。为了解决有效免疫治疗的这些障碍，我们将通过转导慢病毒构建体来遗传修饰自体T细胞，所述慢病毒构建体编码针对两种天然加工表位的高亲和力T细胞受体（TCR），所述两种天然加工表位源自肿瘤抗原MAGE-A3和NY-ESO-1。这些癌症/睾丸肿瘤抗原（CTAgs）在骨髓瘤细胞中频繁且特异性地表达。我们将专门研究这些转导的细胞是否可以在自体干细胞移植（ASCT）后很快安全转移，以及这些基因修饰的T细胞是否在患者中持续存在，功能和靶向骨髓瘤细胞。我们还将使用来那度胺作为骨髓瘤的移植后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随后过继转移“重定向”自体T细胞的这种组合策略可能是骨髓瘤和其他血液肿瘤的有效移植后免疫治疗的平台。 公共卫生相关性：我们的长期目标是开发一种产生临床有效的骨髓瘤免疫应答的策略，以潜在地增加长期缓解和治愈的可能性。我们的假设是，过继转移的扩增/活化的自体T细胞，在遗传上“重定向”到骨髓瘤肿瘤靶点，将是安全的，并可能导致显着的抗肿瘤免疫骨髓瘤自体干细胞移植后。目前的建议是基于我们在移植后过继性T细胞治疗领域的第四项重大临床试验。

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.