Trial Summary
What is the purpose of this trial?CMV cytotoxic T cells (CTLs) manufactured with the Miltenyi CliniMACS Prodigy Cytokine Capture System will be administered in children, adolescents and young adults (CAYA) with refractory cytomegalovirus (CMV) infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), with primary immunodeficiencies (PID) or post solid organ transplant.
Funding Source: FDA OOPD
What safety data is available for CMV-specific CTLs treatment?CMV-specific cytotoxic T lymphocytes (CTLs) have been reported to provide long-term CMV-specific immunity without major side effects, as mentioned in the study on the production of CMV pp65-specific T cells. Additionally, a phase 2 study involving 50 allogeneic hematopoietic stem cell transplant recipients who received donor-derived CMV-specific CTLs showed outcomes compared to controls, suggesting the treatment's potential safety and efficacy. However, detailed safety data specific to adverse effects or complications were not explicitly provided in the available abstracts.46789
Do I have to stop taking my current medications for this trial?The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are receiving steroids at a dose greater than 0.5 mg/kg prednisone equivalent or if you have been treated with certain immunosuppressive drugs or donor lymphocyte infusion recently. It's best to discuss your current medications with the trial team.
Is the treatment Viral Specific Cytotoxic T-Lymphocytes a promising treatment for CMV infection?Yes, Viral Specific Cytotoxic T-Lymphocytes (CTLs) are a promising treatment for CMV infection. They help the immune system fight the virus by targeting and destroying infected cells. Studies show that CTLs can reduce the virus load in the body and protect against CMV disease, especially in patients with weakened immune systems, like those who have had transplants.12347
What data supports the idea that CMV-Specific CTLs for CMV Infection is an effective treatment?The available research shows that CMV-Specific CTLs are effective in reducing the risk of severe CMV disease after bone marrow transplantation. In one study, patients who had detectable CMV-specific CTLs did not develop CMV pneumonia, while 6 out of 10 patients without these CTLs died from it. Another study found that CMV-specific CTLs help control the virus load in renal transplant patients, reducing the risk of CMV disease. These findings suggest that CMV-Specific CTLs can be a protective treatment against CMV infection.12357
Eligibility Criteria
This trial is for children, adolescents, and young adults aged 0.1 to 30.99 years with refractory CMV infection after a stem cell or organ transplant, or those with primary immunodeficiencies. Participants must have tried antiviral therapy without success or cannot tolerate it due to side effects like low white blood cell counts or kidney issues.Inclusion Criteria
I have a family donor who matches me and is CMV positive or has a T-cell response to CMV.
I am between the ages of 0 and 79.
I can do most activities by myself.
I am a woman who can have children and my pregnancy test is negative.
Exclusion Criteria
I have been diagnosed with HIV.
I am not pregnant, breastfeeding, and willing to use birth control during the study.
I have had CMV infection affecting my eyes or brain.
I have been diagnosed with CMV retinitis.
I am mostly bedridden and unable to care for myself.
I am taking steroids equivalent to more than 0.5 mg/kg of prednisone at the time of my treatment.
I have severe acute GVHD or widespread chronic GVHD.
Treatment Details
The study tests the use of virus-specific cytotoxic T-lymphocytes (CTLs) in patients who haven't responded well to standard treatments for CMV infections post-transplantation. These CTLs are developed using a special system and aim to fight off the persistent infection.
1Treatment groups
Experimental Treatment
Group I: Refractory CMVExperimental Treatment1 Intervention
Patients with refractory CMV will be given one dose of CMV specific CTLs. HLA matched donors will get Dose 2.5 ร 10(4) CD3/kg recipient weight; HLA mismatched will get 0.5x10(4) CD3/kg recipient weight. Additional doses may be given for a total of 5 doses if patients do not have a response to the first dose with a reduction in viral load to normal limits.
Viral Specific Cytotoxic T-Lymphocytes is already approved in United States, European Union for the following indications:
๐บ๐ธ Approved in United States as Viral Specific Cytotoxic T-Lymphocytes for:
- Refractory cytomegalovirus (CMV) infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT)
- Primary immunodeficiencies (PID)
- Post solid organ transplant
๐ช๐บ Approved in European Union as CMV-specific CTLs for:
- Refractory cytomegalovirus (CMV) infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT)
- Primary immunodeficiencies (PID)
- Post solid organ transplant
Find a clinic near you
Research locations nearbySelect from list below to view details:
Indiana UniversityIndianapolis, IN
Nationwide Children's HosptialColumbus, OH
Children's Hospital Los AngelesLos Angeles, CA
Medical College of Wisconsin/Children's Hospital of WisconsinMilwaukee, WI
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Who is running the clinical trial?
New York Medical CollegeLead Sponsor
Children's Hospital of PhiladelphiaCollaborator
Medical College of WisconsinCollaborator
Indiana UniversityCollaborator
Washington University School of MedicineCollaborator
Johns Hopkins UniversityCollaborator
Children's Hospital Los AngelesCollaborator
Nationwide Children's HospitalCollaborator
University of California, San FranciscoCollaborator
References
Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. [2021]The high rate of severe cytomegalovirus (CMV) disease after bone marrow transplantation (BMT) is related to the profound immunodeficiency posttransplant. Because cytotoxic T lymphocytes (CTL) have been implicated in resistance to viral infections, we examined the restoration of the CMV-specific CTL response in 20 patients who received bone marrow from HLA-matched, CMV-seropositive donors. Blood specimens were obtained from patients at 1, 2, and 3 months after BMT and from the donors on a single occasion. Peripheral blood mononuclear cells were cocultured with CMV-infected donor-derived fibroblasts for 2 weeks and then tested for cytotoxicity against CMV-infected and uninfected autologous or HLA-mismatched fibroblasts. Cytolytic activity was detected in all 20 donors, with specificity for autologous CMV-infected targets demonstrable in 17 (median CMV-specific lysis at an effector:target ratio of 15:1 was 32%, range 18% to 83%). Specific lysis was mediated by CD8+, class I-restricted T cells, as shown by inhibition with anti-class I monoclonal antibody and by selective depletion of effector cells. By contrast, CMV-specific CTL were detected in only 10 of 20 patients after BMT (median lysis 29% at 3 months post-BMT). None of these 10 patients developed CMV pneumonia, whereas 6 of the 10 patients with an undetectable CMV-specific CTL response after BMT died with CMV pneumonia. These results demonstrate that restoration of CMV-specific CTL responses may require an extended time period after BMT in some patients, and that such patients are at increased risk of developing severe CMV disease. Approaches to reconstitute CMV immunity in BMT patients by adoptive transfer of CMV-specific CD8+ CTL clones derived from the bone marrow donor are now being pursued.
Definition of human cytomegalovirus-specific target antigens recognized by cytotoxic T cells generated in vitro by using an autologous lymphocyte system. [2006]We developed an in vitro system for the generation of human cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) that avoids the necessity of constituting a panel of HLA-typed fibroblasts. Autologous donor leucocytes were coated with CMV antigens and were used as both stimulator and target cells. With the use of this system, CMV-specific effector cells were efficiently generated from seropositive but not seronegative donors. These CMV-specific effectors were HLA-restricted and had characteristics of T cells. Maximum lymphoproliferation preceded the appearance of maximum CTL activity by 3 to 4 days, and a close correlation was seen between both activities. Mouse anti-CMV monoclonal antibodies were used in blocking experiments in an attempt to define target antigens recognized by CMV-specific cytotoxic lymphocytes. Monoclonal antibodies directed against an early CMV membrane antigen, against neutralization epitopes, or against nuclear inclusion body protein all specifically inhibited CMV-sensitized effector cell activity but did not affect influenza virus-specific lysis. Monoclonal antibodies directed against a normal cell determinant or against poliovirus did not affect CMV-specific CTL activity. CMV-immune cytotoxic T cells could be consistently and specifically inhibited in their lytic activity by pretreating antigen-coated target cells with monoclonal antibodies directed against CMV-related proteins.
Cytomegalovirus (CMV)-specific T cell immunity after renal transplantation mediates protection from CMV disease by limiting the systemic virus load. [2006]The role of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTLs) and T helper cells (Th) in controlling CMV infection, as detected by antigenemia assay and polymerase chain reaction (PCR) in blood leukocytes, and CMV disease was investigated in 20 renal transplant recipients. Within 3 months after transplant, CMV-specific CTL and Th responses were demonstrable in 11 (55%) and 15 (75%) patients, respectively; CMV infection was detected by antigenemia and PCR in 19 (95%) patients each. During the month of first CMV detection, there was an inverse correlation between CTL response and antigenemia at >/=20 positive cells/105 leukocytes (P=.007) but no association with lower antigenemia levels or PCR positivity. CMV disease developed in 7 (35%) patients and was associated with high-level antigenemia but was inversely correlated with detection of CTLs (P=.04). After renal transplantation, CMV-specific CTLs limit the systemic virus load as reflected by antigenemia levels and thereby mediate protection from CMV disease.
Adoptive immunotherapy for cytomegalovirus (CMV) disease in immunocompromised patients. [2005]Cytomegalovirus (CMV) reactivation in immune compromised patients such as those undergoing hematopoietic progenitor cell transplantation (HPCT) and those with HIV infections can cause severe morbidity and mortality despite treatment with appropriate antiviral agents. The recovery of Cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) plays an important role in the reconstitution of CMV specific immunity in immunocompromised patients. Recent studies have reported that CMV reactivation can be successfully treated by adoptive transfer of CMV-specific T cell clones from CMV seropositive donors expanded in vitro with CMV infected fibroblasts or lysates of CMV infected cells. Other studies have used immune dominant CMV proteins or peptides to expand CMV-specific cytotoxic T lymphocytes. This review describes the clinical manifestations of CMV disease in immunocompromised patients, recent advances of antiviral therapy for CMV disease, the principals of the induction of cellular immune response to CMV, and the clinical application of CMV immunotherapy.
CMV-specific T cell therapy. [2007]Human cytomegalovirus (CMV) infection continues to be one of the most important and life threatening complications after allogeneic stem cell transplantation (SCT). The reconstitution of CMV-specific T cell responses after SCT has been demonstrated to be protective against the development of CMV disease. To improve T cell immunity against CMV in bone marrow transplant patients, different strategies were explored. On one hand, CMV-specific T cells can be selected from the donor, and can be transferred to the patient without any further in vitro expansion. On the other hand, CMV-specific T cells can be activated and expanded in vitro by stimulation with antigen presenting cells (APCs) loaded with specific proteins or peptides. Here, we review the therapeutic application of CMV-specific T cells to fight CMV infection.
Pharmacotherapy versus T lymphocytes for CMV. [2021]In this issue of Blood, Blyth et al report a phase 2 study in 50 allogeneic hematopoietic stem cell transplant (HSCT) recipients who received donorderived cytomegalovirus (CMV)-specific cytotoxic T cells (CTLs) and compare outcomes with a group of concomitant controls who were transplanted at the trial centers but who did not receive CTLs.
Rapid monitoring of immune reconstitution after allogeneic stem cell transplantation--a comparison of different assays for the detection of cytomegalovirus-specific T cells. [2013]Cytotoxic T cells (CTLs) play an important role in controlling cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The purpose of this study was to compare four different assays to detect CMV antigen-specific T cells for the monitoring of CMV-specific immune reconstitution after HSCT.
Persistence of recipient-derived as well as donor-derived clones of cytomegalovirus pp65-specific cytotoxic T cells long after allogeneic hematopoietic stem cell transplantation. [2014]Cytomegalovirus (CMV)-specific CD8(+) cytotoxic T lymphocytes (CMV-CTLs) play a crucial role in preventing CMV disease. However, the actual in vivo dynamics of CMV-CTL clones after allogeneic hematopoietic stem cell transplantation (alloHCT) are still unclear.
Robust Production of Cytomegalovirus pp65-Specific T Cells Using a Fully Automated IFN-ฮณ Cytokine Capture System. [2022]Cytomegalovirus(CMV)-related diseases are a serious cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). CMV-specific cytotoxic T lymphocytes (CMV-CTLs) have been reported as an alternative to antiviral drugs that provide long-term CMV-specific immunity without major side effects. However, their application has been limited by the prolonged manufacturing process required.