Anti-viral T-cell Therapy by Gamma Capture for High-risk Patients With Acquired or Inherited Immune Defects
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 25
- 试验地点
- 2
- 主要终点
- Grade III-IV Acute GvHD
研究概览
简要总结
The primary purpose of this phase I/II study is to evaluate whether partially matched, ≥1/6 Human Leukocyte Antigens (HLA) -matched, viral specific T cells have efficacy against adenovirus, Cytomegalovirus (CMV), and Epstein Barr Virus (EBV) in subjects who have previously received any type of allogeneic Hematopoietic Cell transplant (HCT) or solid organ transplant (SOT) or have compromised immunity. Reconstitution of anti-viral immunity by donor-derived cytotoxic T lymphocytes has shown promise in preventing and treating infections with adenovirus, CMV, and EBV. However, the weeks taken to prepare patient-specific products, and cost associated with products that may not be used limits their value. This trial will evaluate viral specific T cells generated by gamma capture technology. Eligible patients will include HCT and/or SOT recipients, and/or patients with compromised immunity who have adenovirus, CMV, or EBV infection or refractory viremia that is persistent despite standard therapy. Infusion of the cellular product will be assessed for safety and efficacy.
详细描述
Enrollment for existing UPMC patients.
Ideally, subjects will receive up to ≤1 x 105 (100,000) viable CD3 cells/kg however actual cell dose of infusion will be based upon available cells and subject's clinical picture. Historically, subjects have received all available cells after the gamma capture procedure.
Two-weeks post initial cellular infusion, subject may be eligible to receive additional cellular infusions. If so, either the same or an alternative donor may be considered however, a subject will not receive more than 3 infusions from one donor or exceed 6 infusions in total from all donors. Infusions will be a minimum of 14-days apart. Subjects will not receive additional infusions if they exhibit Graft Versus Host Disease (GvHD) or Cytokine Release Syndrome (CRS) Grade II or higher, according to CTCAE v5.
If a subject is to receive a second infusion, eligibility and baseline data collection will not be repeated for the recipient or original donor, unless necessary per institutional guidelines. Should an alternative donor be selected for an infusion, eligibility of the new donor will need confirmed. Pregnant donors may be considered if medically suitable.
Two weeks post-initial cellular infusion, the following criteria will be assessed to determine if additional infusions are necessary:
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
- 年龄范围
- 1 Month 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient, parent, or legal guardian must have given written informed consent, according to FDA guidelines. For pediatric subject who are developmentally able, assent or affirmation will be obtained, if feasible.
- •Male or female, 1 month through 75 years old, inclusive, at the time of informed consent.
- •Prior allogeneic hematopoietic stem cell transplant (bone marrow, peripheral blood stem cells, single or double cord blood), OR prior solid organ transplant (liver, kidney, lung and/or heart, intestinal, or multivisceral), OR diagnosis of primary immunodeficiency OR current/recent administration of immunosuppressive therapy for cancer or autoimmune disease.
- •Negative pregnancy test for females ≥10 years old or who have reached menarche, unless surgically sterilized. All females of childbearing potential and lactation must agree to use an FDA approved method of birth control for the duration of their participation.
- •Clinical status, at the time of consent, amendable to tapering of steroids to less than 1 mg/kg/day prednisone (or equivalent) prior to cellular infusion.
- •Diagnosis of Adenovirus, CMV, or EBV infection, persistent despite standard therapy.
- •A. Adenovirus Infection or Disease:
- •Active adenovirus infection: (i.e. gastroenteritis, pneumonia, hemorrhagic cystitis, hepatitis, pancreatitis, meningitis) defined as the demonstration of adenovirus by biopsy specimen from affected site(s) (by culture or histology), or the detection of adenovirus by culture, PCR or direct fluorescent antibody stain in fluid in the presence of worsening or persistent clinical or imaging findings despite at least 14 days of appropriate antiviral therapy (i.e. cidofovir, brincidofovir, or other available pharmacological agents) OR
- •Refractory adenoviremia: defined as DNAemia >5000 copies/mL or <1 log decrease after at least 2 weeks of appropriate antiviral therapy (i.e. cidofovir, brincidofovir, or other available pharmacological agents) OR
- •Intolerance of or contraindication to antiviral medications.
- •B.CMV Infection or Disease:
- •Active CMV infection: (i.e. pneumonia, meningitis, retinitis, hepatitis, hemorrhagic cystitis, and/or gastroenteritis) defined as the demonstration of CMV by biopsy specimen from affected site(s) (by culture or histology) or the detection of CMV by culture, PCR or direct fluorescent antibody stain in fluid in the presence of worsening or persistent clinical or imaging findings despite at least 14 days of appropriate antiviral therapy (i.e. Foscarnet, ganciclovir, cidofovir, or other available pharmacological agents) OR
- •Refractory CMV viremia: defined as the continued presence of DNAemia, with ≥2,000 IU/mL or <1 log decrease after at least 14 days of appropriate antiviral therapy (i.e. Foscarnet, ganciclovir, cidofovir, or other available pharmacological agents) OR
- •Intolerance of or contraindication to antiviral medications.
- •C. EBV Infection or Disease:
- •Biopsy proven lymphoma or posttransplant lymphoproliferative disease with EBV genomes detected in tumor cells by immunocytochemistry (i.e. EBER positive) or in situ PCR, OR
- •Clinical or imaging findings consistent with EBV lymphoma and associated elevated EBV viral load in peripheral blood in a patient where biopsy is deemed too high risk, OR
- •Failure of antiviral therapy, as determined by one of the two bullets below after three weeks of anti-CD20 targeted therapy such as Rituximab.
- •i. There was an increase or less than 50% response at sites of lymphoma disease or lymphoproliferation.
- •ii. There was a rise or a fall of less than 50% in EBV viral load in peripheral blood of PTLD patients.
排除标准
- •Received Antithymocyte Globulin (ATG) or Alemtuzumab within 28 days of viral-specific T cell infusion and a lack of evidence of T cell survival, defined by <10 CD3+ T cells/uL (in unique situations, plasmapheresis may be considered).
- •Active acute GVHD grades II-IV.
- •Received donor lymphocyte infusion, with the exception of a fraction of an umbilical cord blood, within 14 days of viral-specific T cell infusion. Subjects receiving a fraction of an umbilical cord blood within 14 days of the viral-specific T cell infusion will not be excluded.
- •Active and uncontrolled relapse of malignancy (other than EBV+ post-transplant lymphoproliferative disorder or lymphoma).
- •Received an investigational product in the preceding 2 weeks (prior to infusion) that may impact Viral Specific T-cells (VST) survival.
- •Females of child bearing potential must not be lactating.
- •Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks to participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study.
研究组 & 干预措施
Viral Specific T-Lymphocytes
Viral Specific T-Lymphocytes Peripheral blood mononuclear cells will be collected from the donor and loaded onto our Miltenyi Biotec CliniMACS Prodigy® or CliniMACS® Plus where they will be stimulated in vitro with viral-specific antigen(s). The cells are then immunomagnetically labeled with interferon gamma via the cytokine capture system. By this method, viral specific, gamma-secreting T cells, are captured in a closed, sterile system.
干预措施: Specific T- Lymphocytes (Biological)
结局指标
主要结局
Grade III-IV Acute GvHD
时间窗: 6 month from first cellular infusion
The number of patients who develop Grade III-IV acute graft versus host disease (GVHD) attributed to the viral specific T cells.
Clinical response to treatment of viral infection
时间窗: 6 months from first cellular infusion
Rate of Elimination or reduction of oxygen dependence identified at baseline
Grade III-IV Acute GvHD
时间窗: Day 0
The number of patients who develop Grade III-IV acute graft versus host disease (GVHD) attributed to the viral specific T cells.
Grade III-IV Acute GvHD
时间窗: 1 month from first cellular infusion
The number of patients who develop Grade III-IV acute graft versus host disease (GVHD) attributed to the viral specific T cells.
Grade III-IV Acute GvHD
时间窗: 3 month from first cellular infusion
The number of patients who develop Grade III-IV acute graft versus host disease (GVHD) attributed to the viral specific T cells.
Clinical response to treatment of viral infection
时间窗: 1 month from first cellular infusion
Rate of Elimination or reduction of oxygen dependence identified at baseline
Clinical response to treatment of viral infection
时间窗: 3 month from first cellular infusion
Rate of Elimination or reduction of oxygen dependence identified at baseline
次要结局
- Incidence of Graft rejection(6 months after last cellular infusion)
- Incidence of severe or extensive chronic GVHD(6 months from first cellular infusion)
- 1-year overall survival from first cellular infusion (continuous)(First cellular infusion to 1 year post first cellular infusion)
- Incidence of Mechanical ventilation exceeding 48 hours(6 months after last cellular infusion)
- Usage of concomitant antiviral agents(First cellular infusion to 1 year post first cellular infusion)
- Immune reconstitution with focus on adaptive T cell immunity and viral-specific responses(3 months following first cellular infusion)
- Incidence of Graft rejection(3 months after last cellular infusion)
- Incidence of Mechanical ventilation exceeding 48 hours(3 months after last cellular infusion)
- Immune reconstitution with focus on adaptive T cell immunity and viral-specific responses(1 month following first cellular infusion)
研究者
Paul Szabolcs
Chief, Division of Blood and Marrow Transplantation and Cellular Therapies, Medical Director of the Stem Cell Laboratory
University of Pittsburgh