Allogeneic Immunotherapy for cancer and nonmalignant hem

癌症和非恶性下肢的同种异体免疫疗法

• 批准号: 7321313
• 负责人: RICHARD CHILDS
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 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/7321313
• 关键词: Allogeneic; Immunotherapy; cancer; nonmalignant; hem

The ability of allogeneic lymphocytes to target and eradicate leukemia cells has been established as a true biological entity over the past ten (20) years. Whether such effects can be generated against non-hematological "solid" malignancies remains unexplored. We initiated a clinical trail using a non-myeloablative approach of allogeneic stem cell transplantation in patients with treatment refractory metastatic renal cell carcinoma (RCC). Definitive evidence for an allogeneic graft-versus-RCC effect has been demonstrated with complete regression of large metastasis observed in some patients. Recently we demonstrated a similar effect to have occurred in a patient with colon carcinoma and prostate cancer. We have subsequently initiated studies investigating immune reconstitution in those demonstrating an anti-RCC effect in attempts to identify both the effector cell populations mediating these regressions as well as their target antigens. Our laboratory has confirmed the expression of minor histocompatibility antigens on the surface of kidney cancer cells. We demonstrated that cytotoxic T-cell clones with specificity for minor antigens are capable of killing RCC cells in patients having a GVT effect post transplant. We also were able to expand T-cell clones in two responding patients that recognized either tumor cells specifically or broadly expressed antigens present on both patient hematopoietic cells and RCC cells. These observations provide the first insight into the immune mechanisms mediating the regression of metastatic cancer following non-myeloablative allogeneic transplantation. Using c-DNA expression cloning, we have recently identified a novel tumor antigen derived from a human endogenous retrovirus over expressed on RCC cells called CT-RCC. This antigen is not expressed on normal tissues and therefore could potentially serve as a target for a future kidney cancer vaccine. We are currently attempting to identify factors regulating expression of this newly identified tumor antigen. Recently we have developed a murine model of allogeneic SCT in hosts bearing metastatic RCC, in which reproducible GVT effects occur extending animal survival compared to recipients of autologous transplants. Post transplant tumor vaccination studies are being conducted in this model, as well as investigations into the impact of inhibiting angiogenesis in the first few months of transplantation using PDGF, VEGF, and EGF-R tyrosine kinase inhibitors. Our group has recently shown that KIR incompatible NK cells are cytotoxic to solid tumor cells in vitro. Using the above mentioned animal model, we have shown that a single infusion of alloreactive NK cells can significantly reduce GVHD and prolong survival in mice with RCC undergoing allogeneic HCT. Based on these findings, we plan to evaluate whether GVT effects aginanst RCC can be enhanced after allogeneic HCT by adoptively infusing escalating doses of donor NK cells. We are also exploring methods to sensitize solid tumors to NK cell attack by altering the phenotype of tumor cells through targeted gene induction. Recently we showed that bortezomib and depsipeptide sensitize tumors to NK cell cytotoxity by enhancing NK-cell mediated TRAIL killing. This sensitization appears to overcome NK inhibition that is mediated through KIR-KIR ligand interactions. We have also developed a method to expand by > 4 logs NK cells from healthy donors for adoptive infusion in future NK-Cell based adoptive immunotherapy trials. Based on these findings, this year we were awarded a 2 year bench to bedside award to scale up our NK cell expansions to test whether bortezomib could be used to sensitize patient's tumors to adoptive autologous NK cell infusions. Our group continues to explore the use of allogeneic SCT in patients with nonmalignant diseases such as PNH or ATGF-Refractory severe aplastic anemia. We have also recently shown that PNH can be cured following nonmyeloablative stem cell transplantation. In vitro studies conducted in our laboratory have shown PNH cells are equally sensitive to allogeneic immune attack as normal GPI-positive immune cells. At present, 29 patients with SAA/PNH have been transplanted with a day 100 TRM of 0%.

在过去的十（20）年中，同种异体淋巴细胞靶向和根除白血病细胞的能力已被确立为一种真正的生物实体。这种效果是否可以对非血液学“实体”恶性肿瘤产生仍然没有探索。我们在难治性转移性肾细胞癌（RCC）患者中开展了一项使用非清髓性异基因干细胞移植方法的临床试验。同种异体移植物抗RCC效应的有力证据已被证实，在一些患者中观察到的大转移完全消退。最近，我们证明了一个类似的效果，发生在结肠癌和前列腺癌患者。随后，我们开始了研究免疫重建在那些表现出抗RCC效果，试图确定介导这些回归的效应细胞群体以及它们的靶抗原。我们的实验室已经证实在肾癌细胞表面表达次要组织相容性抗原。我们证明了对次要抗原具有特异性的细胞毒性T细胞克隆能够杀死移植后具有GVT效应的患者中的RCC细胞。我们还能够在两个应答患者中扩增T细胞克隆，其识别存在于患者造血细胞和RCC细胞上的肿瘤细胞特异性或广泛表达的抗原。这些观察结果提供了第一次深入了解免疫机制介导的非清髓性异基因移植后转移性癌症的消退。使用c-DNA表达克隆，我们最近已经确定了一种新的肿瘤抗原来自人内源性逆转录病毒在RCC细胞上过表达，称为CT-RCC。这种抗原在正常组织中不表达，因此可能成为未来肾癌疫苗的靶点。我们目前正试图确定调节这种新发现的肿瘤抗原表达的因子。 最近，我们在携带转移性RCC的宿主中开发了一种同种异体SCT的小鼠模型，与自体移植受体相比，其中出现了可重复的GVT效应，延长了动物的生存期。在该模型中进行移植后肿瘤疫苗接种研究，以及在移植的前几个月使用PDGF、VEGF和EGF-R酪氨酸激酶抑制剂抑制血管生成的影响的研究。我们的小组最近表明，KIR不相容的NK细胞在体外对实体瘤细胞具有细胞毒性。使用上述动物模型，我们已经表明，单次输注同种异体反应性NK细胞可以显着减少GVHD，并延长接受同种异体HCT的RCC小鼠的生存期。基于这些发现，我们计划评估是否可以通过过继输注递增剂量的供体NK细胞来增强同种异体HCT后GVT对RCC的作用。 我们还在探索通过靶向基因诱导改变肿瘤细胞表型来使实体瘤对NK细胞攻击敏感的方法。最近，我们发现硼替佐米和缩酚酸肽通过增强NK细胞介导的TRAIL杀伤而使肿瘤对NK细胞的细胞毒性敏感。这种致敏似乎克服了通过KIR-KIR配体相互作用介导的NK抑制。我们还开发了一种方法，用于在未来基于NK细胞的过继免疫治疗试验中，将来自健康供体的NK细胞扩增> 4 log用于过继输注。基于这些发现，今年我们获得了为期2年的临床试验奖，以扩大我们的NK细胞扩增，以测试硼替佐米是否可用于使患者的肿瘤对过继性自体NK细胞输注敏感。 我们的研究小组继续探索同种异体SCT在非恶性疾病如PNH或ATGF难治性重型再生障碍性贫血患者中的应用。我们最近也发现PNH可以通过非清髓性干细胞移植治愈。我们实验室进行的体外研究表明，PNH细胞对同种异体免疫攻击的敏感性与正常GPI阳性免疫细胞相同。目前，29例SAA/PNH患者已接受移植，100天TRM为0%。