Autologous Dendritic Cell Therapy for Type 1 Diabetes Suppression: A Safety Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 2
- 主要终点
- The trial is designed to assure that the toxicity rate is acceptably low to warrant further study of the cell vaccine in efficacy trials.
研究概览
简要总结
The proposed studies describe a randomized trial to evaluate the safety of a new diabetes-suppressive cell vaccine, consisting of autologous monocyte-derived dendritic cells treated ex vivo with antisense phosphorothioate-modified oligonucleotides targeting the primary transcripts of the CD40, CD80 and CD86 co-stimulatory molecules (immunoregulatory DC; iDC). The hypothesis to be tested in this study is that iDC are safe and without toxicity in established type 1 diabetic patients.
Fifteen (15) individuals exhibiting fully-established, insulin-dependent type 1 diabetics, without any diabetes-related complications, infectious disease, or other medical anomaly, will be enrolled to establish safety of the approach. 7/15 volunteers will be administered autologous control dendritic cells and 8/15 will be administered iDC. The study is anticipated to be complete by twelve (12) months.
Currently, other than a humanized anti-CD3 antibody with considerable side effects, there is no other means to reverse new-onset type 1 diabetes. These studies will be the first ever to employ autologous dendritic cell transfer to suppress an autoimmune disease and to perhaps reverse it early on in the clinical process.
详细描述
In this study, volunteers with established type 1 diabetes that requires insulin replacement who do not exhibit any diabetes-related complications or any other clinical pathology will first undergo complete physical, biochemical and immunological evaluation. Monocyte-derived autologous dendritic cells will be obtained following leukapheresis. The dendritic cells will be treated ex vivo with the antisense oligonucleotides and cryopreserved in aliquots for subsequent intradermal administration into sites closest to the physical location of the pancreas inside the body. Physiologic, biologic and immunologic responses to the dendritic cell vaccine will be evaluated over the period of the trial. The first group of volunteers will receive autologous dendritic cells without any ex vivo treatment (7/15) and the second group will be administered iDC (8/15). If there is no evidence of toxicity or adverse events associated with the dendritic cell vaccine, and only upon FDA and IRB approval we will initiate a new study comparing efficacy of control DC and iDC in improving glycemia and reversing autoimmunity in new-onset patients.
Currently, other than a humanized anti-CD3 antibody with considerable side effects, there is no other means to reverse new-onset type 1 diabetes. These studies will be the first ever to employ autologous dendritic cell transfer to suppress an autoimmune disease and to possibly reverse it early on in the clinical process.
We propose to ascertain the safety of autologous dendritic cells treated ex vivo with antisense oligonucleotides targeting the primary transcripts of the CD40, CD80 and CD86 co-stimulatory molecules (we term these cells "immunoregulatory dendritic cells; iDC) first in volunteers with established type 1 diabetes.
Personality traits and emotional stability have been linked to treatment adherence in other medical populations (e.g. Christensen et al, 2002; Dew et al., 2001). In that adherence to this protocol (e.g. remaining in the study) by this small sample will impact significantly on results and that the treatment itself may affect mood, we will assess personality traits at baseline and monitor mood throughout the study period.
2.2 Significance of the studies: We do not anticipate any safety issues with this approach but we must be cautious at all levels given that this is immunomodulation therapy. At the very least, data will be obtained on whether the success we have observed with the iDC in NOD mice can be eventually adapted in other protocols aimed to restore normoglycemia or improve glycemic control along with increased prevalence of putative immunoregulatory T cells in recently-diagnosed humans.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Patients with established type 1 diabetes mellitus who meet all inclusion criteria are eligible for enrollment in the study.
- •All patients enrolled must be on insulin replacement therapy.
- •Written informed consent conforming to the institutional guidelines obtained from the patient.
- •Documented evidence of insulin-requiring type 1 diabetes of >5 years duration.
- •Adequate immune competence, as indicated by positive reaction to one or more of the common DTH skin tests that are part of the Multitest CMITM test system (Pasteur-Merieux Connaught) and as indicated by the manufacturer. Also, proof of vaccination for tetanus (no more than 10 years must have elapsed between tetanus vaccination and the onset of this study).
- •Adequate hematologic function:
- •Absolute neutrophil count > 1,000/mm3
- •Absolute lymphocyte count > 1,000/mm3
- •Hemoglobin > 9 gm/dl
- •Platelets > 100,000/mm3
- •Liver function tests:
- •Bilirubin (total) < 1.7 mg/dl
- •Alkaline phosphatase < 78 u/L (2 x ULN)
- •SGOT < 54 u/L (2 x ULN)
- •Lactic dehydrogenase < 180 u/L (2 x ULN)
- •Kidney profile:
- •Serum electrolytes
- •Sodium 135-145 mEq/L
- •Potassium 3.5-5.0 mEq/L
- •Bicarbonate 21-28 mEq/L
- •Chloride 100-108 mmol/L
- •Serum creatinine <4.5 mg/dL (3 x ULN)
- •BUN 8-25 mg/dL
- •No prior history of radiation therapy, immunotherapy, or chemotherapy
- •Evidence of prior immunization to tetanus
- •Absence of HIV, HSV, HBV, HCV viral infections
- •At least four weeks since any prior radiation , immunotherapy or chemotherapy
排除标准
- •One or more of the Eligibility Criteria are not met.
- •A significant history or current evidence of cardiac disease including, but not limited to, congestive heart failure, coronary artery disease, angina pectoris, uncontrolled hypertension, serious arrhythmias; or myocardial infarction within the previous six months.
- •Evidence of active infection requiring antibiotic therapy.
- •History of other concurrent diseases.
- •Pregnant or lactating women.
- •Patients requiring systemic corticosteroids
- •Any other immune disorder including but not limited to other autoimmune diseases like rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, or ankylosing spondylitis
- •Pregnancy
- •History of radiation therapy, immunotherapy, or chemotherapy
- •Breastfeeding
- •The following therapies cannot be administered while patients are undergoing treatment on this protocol:
- •radiation therapy
- •chemotherapy
- •corticosteroids (except when administered in life-threatening circumstances) other particle or cell vaccine therapies
- •At the time of screening, the patients will be tested for evidence of the following viral infections: HIV, HBV, HCV, herpes, CMV and EBV. In addition, female volunteers will be asked to provide documentation from their physician stating that they have not tested positive for the HPV viral infection. Only patients testing negative for ALL these viral infections will be further considered. Should any volunteer be excluded on grounds of positivity for any of these infectious agents, they will be immediately notified and strongly advised to consult their physician. The data and the records will be maintained under lock and in the study participation file of the volunteer until the volunteer confirms in writing that they have notified their physician. At that time, these specific data may be submitted to the patient's physician ONLY DIRECTLY BY THE VOLUNTEER upon written request to the study principal investigator or immediately destroyed.
结局指标
主要结局
The trial is designed to assure that the toxicity rate is acceptably low to warrant further study of the cell vaccine in efficacy trials.
时间窗: June 2011
次要结局
未报告次要终点