Most Closely HLA Matched Allogeneic Virus Specific Cytotoxic T-Lymphocytes (CTL) to Treat Persistent Reactivation Or Infection With Adenovirus, CMV and EBV After Hemopoietic Stem Cell Transplantation (HSCT)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 8
- 主要终点
- The primary purpose of the study is to assess the safety of administering CHM-CTLs in transplant patients with EBV, CMV, or adenovirus infection. We have elected to use a dose of 2 x 10^7 CHM-CTLs/m2.
研究概览
简要总结
This trial is designed to evaluate the feasibility, safety and efficacy of most closely HLA-matched multivirus specific CTL lines (CHM-CTLs) in HSCT patients with EBV, CMV or adenovirus infections that are persistent despite standard therapy.
The primary objective of the study is to assess safety and feasibility of administering CTLs. Survival data will be collected by asking the transplant center to submit the routine Transplant Essential Data form that is sent to the Stem Cell Transplant Outcomes Database at 100 days and 1 year and includes data on survival status and other outcome measures.
详细描述
Patients may be screened for study entry when they have persistent disease despite standard therapy as defined in the inclusion criteria. At that stage a search will be done of the available lines. Lines were generated from HSCT donors who consented to the use of CTLs not required for their recipient for research or from normal donors. All donors were screened and deemed to be eligible as transplant donors. We will also manufacture additional lines with the goal of covering common HLA types and will consult with the NMDP to determine what HLA types would be desirable. Additional donors will be screened by a transplant donor center physician and must be deemed eligible before a line can be manufactured.
CTL Lines: We will use trivirus specific CTL lines generated as described previously. Generation of trivirus-specific CTL lines requires the generation of several different components from PBMC. The CTL line will be derived from donor peripheral blood T cells, by multiple stimulations with antigen-presenting cells (APCs) presenting CMV, EBV and adenovirus antigens and expansion with interleukin-2 (IL-2). The APCs used to stimulate and expand the CMV-specific T cells will be derived from patient mononuclear cells and B lymphocytes.
To initiate the trivirus-specific CTL line, PBMC will be transduced with an adenovirus vector (Ad5f35-pp65) expressing the immunodominant antigen of CMV, pp65. The monocyte fraction of PBMC expressed and presented CMV-pp65 peptide epitopes to the CMV-specific T cell fraction of the PBMC, while the virion proteins from the adenovirus vector were processed and presented to the adenovirus-specific T cell fraction.
To expand trivirus -specific T cells we used EBV-transformed B lymphoblastoid cell lines (EBV-LCLs) transduced with Ad5f35-pp65. This transduction allows the EBV-LCLs to present CMV-pp65 and adenovirus virion peptides to the T cells as well as endogenously expressed EBV antigens.
EBV-LCLs are derived from PBMC-B lymphocytes by infection with a clinical grade, laboratory strain of Epstein-Barr virus (EBV). About 5 x 10^6 PBMC, or 5 to 10 mLs of blood is required to generate the EBV-LCL
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Pts will be eligible following any type of allogeneic transplant if they have CMV, adenovirus or EBV infection persistent to standard therapy (as defined below).
- •Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells or single or double cord blood within 18 months.
- •CMV, adenovirus or EBV infection persistent despite standard therapy
- •For CMV infection: i.Pts with CMV disease: defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) or the detection of CMV by culture or direct fluorescent antibody stain in bronchoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates OR ii. Failure of antiviral therapy: defined as the continued presence of pp65 antigenemia (>1+ cell/100,000 cells) or DNAemia (as defined by reference lab performing PCR assay but usually >400 copies/ml) after at least 7 days of antiviral therapy OR iii. Relapse after antiviral therapy defined as recurrence of either pp65 antigenemia or DNAemia after at least 2 weeks of antiviral therapy iv. For CMV infection, standard therapy is defined as 7 days therapy with Ganciclovir, Foscarnet or Cidofovir for patients with disease or recurrence after 14 days therapy
- •For EBV infection: i. EBV infection is defined as:
- •Biopsy proven lymphoma with EBV genomes detected in tumor cells by immunocytochemistry or in situ PCR OR
- •Or clinical or imaging findings consistent with EBV lymphoma and elevated EBV viral load in peripheral blood. ii. For EBV infection, standard therapy is defined as rituximab given at 375mg/m^2 in patients for 1-4 doses with a CD20+ve tumor iii. Failure is defined as:
- •There was an increase or less than 50% response at sites of disease for EBV lymphoma OR
- •There was a rise or a fall of less than 50% in EBV viral load in peripheral blood or any site of disease
- •For adenovirus infection or disease: i. Adenovirus infection is defined as the presence of adenoviral positivity as detected by PCR, DAA or culture from ONE site such as stool, blood, urine, or nasopharynx OR ii. Adenovirus disease will be defined as the presence of adenoviral positivity as detected by culture from two or more sites such as stool or blood or urine or nasopharynx iii. Standard therapy is defined as 7 days therapy with Cidofovir (if renal function permits this agent to be given) iv. Failure is defined as a rise or a fall of less than 50% in viral load in peripheral blood or any site of disease as measured by PCR or any other quantitative assay)
- •Pts with multiple CMV, EBV or Adenovirus infections are eligible given that each infection is persistent despite standard therapy as defined above. Patients with multiple infections with one persistent infection and one controlled infection are eligible to enroll.
- •Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone.
- •Written informed consent from patient, parent or guardian.
- •Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).
- •The informed consent process will begin at recognition of subject eligibility and consent will be obtained per institutional practices before study therapy is initiated. Subjects will initially sign a screening consent to enable a search to be made for a line. If a line is available they will sign the treatment consent.
- •Up to 4 additional doses can be administered if a partial response is obtained and patient meets eligibility criteria for subsequent infusions. The minimum interval between subsequent infusions is 2 weeks.
- •Donors will be eligible if they meet eligibility criteria for blood donors on history and exam by a transplant donor physician and have negative infectious diseases testing.
排除标准
- •For initial CTL and subsequent infusions:
- •Patients receiving ATG, or Campath or other immunosuppressive monoclonal antibodies within 28 days of screening for enrollment.
- •Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.
- •Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- •Patients who have received donor lymphocyte infusion (DLI) within 28 days.
- •Patients with active acute GVHD grades II-IV.
- •Active and uncontrolled relapse of malignancy
- •Donors will be ineligible if they do not meet eligibility criteria for blood donors on the donor questionnaire or have positive infectious diseases testing on any of the tests outlined in the inclusion criteria.
研究组 & 干预措施
Trivirus Specific CTLs for EBV, CMV and Adenovirus Infection
If a patient has a partial response they are eligible to receive up to 4 additional doses at biweekly intervals. These doses would come from the original infused line if sufficient vials were available but may come from another line if there are insufficient cells in the original line.
干预措施: Trivirus Specific CTLs for EBV, CMV and Adenovirus Infection (Biological)
结局指标
主要结局
The primary purpose of the study is to assess the safety of administering CHM-CTLs in transplant patients with EBV, CMV, or adenovirus infection. We have elected to use a dose of 2 x 10^7 CHM-CTLs/m2.
时间窗: 1 year
次要结局
未报告次要终点
研究者
Helen Heslop
Principal Investigator
Baylor College of Medicine