Allogeneic T cells Transduced with an Anti-CD19 Chimeric Antigen Receptor

用抗 CD19 嵌合抗原受体转导的同种异体 T 细胞

• 批准号: 9153903
• 负责人: James Kochenderfer
• 金额: $ 20.23万
• 依托单位: DIVISION OF BASIC 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/9153903
• 关键词: Acute Lymphocytic Leukemia; Allogenic; American; Antigen Receptors; B lymphoid malignancy; B-Cell Lymphomas; Blood; Bone Marrow Transplantation; Bone marrow biopsy; CD19 Antigens; CD19 gene; CD3 Antigens; Cardiac; Cell Count; Cell Lineage; Cell Transplants; Cells; Chronic Lymphocytic Leukemia; Clinical Trials; Development; Diffuse; Disease remission; Donor Lymphocyte Infusion; Donor person; Dose; Fatigue; Fever; Genetic Engineering; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hypercellular Bone Marrow; Hypotension; Hypoxemia; Infusion procedures; Interferon Type II; Interleukin-2; Learning; Left Ventricular Function; Lymphatic Diseases; Magnesium; Malignant Neoplasms; Mantle Cell Lymphoma; Manuscripts; Marrow; Molecular; Mononuclear; Partial Remission; Patients; Phosphorus; Proteins; Recruitment Activity; Refractory; Relapse; Research; Residual state; Resistance; Serum; Societies; Stem cell transplant; T cell therapy; T-Lymphocyte; Toxic effect; Transplantation; Tumor Lysis Syndrome; Uric Acid; X-Ray Computed Tomography; abstracting; cellular transduction; chemotherapy; chimeric antigen receptor; experience; follow-up; human old age (65+); improved; international center; leukemia; leukemia/lymphoma; lymph nodes; meetings; older men; research study; second transplant; vector

The main focus of this project is a clinical trial in which patients that have relapsed or persistent B-cell malignancies after allogeneic stem cell transplantation and at least one standard donor lymphocyte infusion. These patients all have extremely advanced malignancies that have proven to be resistant to all standard therapies. The project resulted in one abstract that was presented at the American Society of Blood and Marrow Transplantation and The Center for International Blood and Marrow Transplant Research tandem meeting in 2011. A manuscript describing the results of patients on this study was submitted 2 weeks ago. We are conducting a clinical trial in which patients receive infusions of allogeneic T cells that are genetically modified with a gammaretroviral vector to express a chimeric antigen receptor (CAR) that recognizes the B-cell antigen CD19. The first patient treated on this trial was a 65 year-old man with chronic lymphocytic leukemia (CLL) who relapsed after HLA-matched unrelated donor hematopoietic stem cell transplantation. Following the relapse, the patient received 4 donor lymphocyte infusions (DLIs) with a maximum CD3+ cell dose of 2.9x10e7 per kg and then a second stem cell transplant from the original donor. An objective remission of the leukemia did not occur after any of the DLIs or the second transplant. Five months after the second transplant, when his CLL was progressing, the patient received an infusion of 6.2x10e7 (1x10e6 cells per kg) allogeneic anti-CD19-CAR-transduced T cells derived from his unrelated transplant donor. Thirty-nine percent of the infused cells expressed the anti-CD19 CAR, and the cells produced interferon-gamma and IL-2 in a CD19-specific manner. The patient did not receive any other therapy in conjunction with the CAR-transduced T cells. From 6 to 12 days after the CAR-transduced T cell infusion, the patient experienced fevers, fatigue, mild hypoxemia, and intermittent mild hypotension. Increases in serum magnesium, phosphorous, and uric acid consistent with tumor lysis syndrome occurred. A decrease in cardiac left ventricular function developed, which was improving at last follow-up. The patients blood B cell count decreased from 286 cells per microliter before the CAR-transduced T cell infusion to 0 cells per microliter 26 days after the cell infusion. Before the CAR-transduced T cell infusion, CLL cells made up 80-90 percent of the patients hypercellular bone marrow. A bone marrow biopsy performed 26 days after the cell infusion showed a normocellular marrow, nearly absent B-lineage cells, and no evidence of CLL. CT scans revealed a greater than 50 percent decrease in the size of multiple lymph nodes after the CAR-transduced T cell infusion, but residual adenopathy was present. CAR-transduced cells were not detected in the patients blood by quantitative PCR during the first week after the T cell infusion, but made up 0.98 percent of blood mononuclear cells 11 days after the infusion. These results are encouraging for further development of anti-CD19-CAR-expressing T cells as a treatment for relapse after allogeneic stem cell transplantation. We have treated 14 additional patients on this clinical trial. A patient with CLL has obtained a complete remission that is ongoing 9 months after infusion of 1.5x106 CAR+ T cells/kg. Another patient with mantle cell lymphoma achieved a partial remission after infusion of anti-CD19 CAR T cells. In the past year, we have continued to escalate the dose of T cells administered to patients on this trial, and we have acheived the maximum planned dose of the trial. Of the 10 patients treated in the past year, 1CLL patient has an ongoing PR of 15 months duration, 4/5 patients with acute lymphoid leukemia (ALL) that was refractory to chemotherapy have acheived a molecular complete remission. We have treated another patient with mantle cell lymphoma and 3 other patients with diffuest large B-cell lymphoma. One diffuse large B-celllymphoma patient treated in the past year is in an ongoing CR. This trial is significant because unlike most trials of anti-CD19 chimeric antigen receptors, it does not include chemotherapy, so it gives a pure assessment of the activity of the anti-CD19 CAR T cells. We continue recruit more patients for this trial. We are obtaining important information on toxicity and predictors of successful therapy with each patient. A manuscript covering this trial has been submitted in the past month.

该项目的主要重点是一项临床试验，该试验在同种异体干细胞移植后复发或持续的B细胞恶性肿瘤和至少一项标准供体淋巴细胞输注。这些患者都有极其晚期的恶性肿瘤，这些恶性肿瘤已被证明对所有标准疗法具有抵抗力。该项目产生了一个摘要，该摘要是在2011年在美国血液和骨髓移植学会以及国际血液和骨髓移植研究串联会议上提出的。两周前提交了一项描述患者结果的手稿。我们正在进行一项临床试验，其中患者接受了同种异体T细胞的输注，这些T细胞被γ逆转录病毒载体遗传修饰，以表达识别B细胞抗原CD19的嵌合抗原受体（CAR）。在这项试验中接受治疗的第一位患者是一名65岁的男性患有慢性淋巴细胞性白血病（CLL），后者在HLA匹配的无关供体造血干细胞移植后复发。复发后，患者接受了4个供体淋巴细胞输注（DLIS），最大CD3+细胞剂量为每公斤2.9x10e7，然后是原始供体的第二个干细胞移植。在任何DLI或第二次移植后，都不会出现白血病的客观缓解。第二次移植后五个月，当他的CLL进展时，患者接受了6.2x10E7（每公斤1x10E6细胞）的同种异体抗CD19-CD19-CAR转导的T细胞，这些T细胞源自其无关的移植供体。 39％的注入细胞表达了抗CD19 CAR，并且细胞以CD19特异性方式产生了干扰素 - γ和IL-2。该患者没有与CAR转导的T细胞一起接受任何其他疗法。汽车转导的T细胞输注后6到12天，患者经历了发烧，疲劳，轻度低氧血症和间歇性轻度低血压。与肿瘤裂解综合征一致的血清镁，磷和尿酸的增加。心脏左心室功能的降低会降低，最终随访正在改善。患者血液B细胞计数从每微氧化液的286个细胞降低，然后在CAR转导的T细胞输注到细胞输注后26天后每微氧纤维的0细胞。在转导T细胞输注之前，CLL细胞占高细胞骨髓的80-90％。细胞输注后26天进行的骨髓活检显示出正常的细胞骨髓，几乎没有B型细胞，没有CLL的证据。 CT扫描显示，在CAR转导的T细胞输注后，多个淋巴结的大小降低了50％以上，但存在残留的腺病。在T细胞输注后的第一周，未通过定量PCR检测到CAR诱导的细胞，但在输注后11天占0.98％的血液单核细胞。这些结果令人鼓舞，以进一步开发抗CD19-表达T细胞作为同种异体干细胞移植后复发的一种治疗方法。我们在这项临床试验中还治疗了14名患者。 CLL患者已获得完全缓解，该缓解措施在输注1.5x106 CAR+ T细胞/kg后进行了9个月的持续缓解。另一位地幔细胞淋巴瘤患者在输注抗CD19 CAR T细胞后已部分缓解。在过去的一年中，我们继续在此试验中升级给患者的T细胞剂量，并且已经实现了该试验的最大计划剂量。在过去一年中接受治疗的10例患者中，1CLL患者的持续性PR持续15个月，4/5例急性淋巴白血病患者（所有）对化学疗法难治性的患者已实现了分子完全缓解。我们已经治疗了另一位接受地幔细胞淋巴瘤的患者和其他3例DIFFUEST大型B细胞淋巴瘤的患者。过去一年中接受治疗的一名弥漫性大型B-囊肿患者是正在进行的CR。该试验很重要，因为与大多数抗CD19嵌合抗原受体试验不同，它不包括化学疗法，因此它纯粹评估了抗CD19 CAR T细胞的活性。我们继续招募更多的患者参加这项试验。我们正在获取有关每位患者成功治疗的毒性和预测指标的重要信息。过去一个月提交了涵盖此试验的手稿。