CMV-Specific CTLs for CMV Infection

Recruiting at 9 trial locations

Overseen By Mitchell S Cairo, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: New York Medical College

Must not be taking: Steroids, Thymoglobulin, Alemtuzumab, others

Disqualifiers: Acute GVHD, Poor performance, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Up to 5 doses

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment using special immune cells, called cytotoxic T-lymphocytes (CTLs), to combat difficult-to-treat cytomegalovirus (CMV) infections. The focus is on children, adolescents, and young adults who have undergone a transplant and cannot clear the infection with standard antiviral medicines. Ideal candidates for this trial include those with persistent CMV infections despite at least two weeks of treatment or those who cannot tolerate current antiviral medications. The trial will investigate whether these CTLs can reduce the virus to normal levels, offering new hope for those with stubborn infections. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients with certain conditions or treatments, like those receiving steroids or certain immunosuppressive therapies, are excluded from participation.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that special immune cells called CMV-specific cytotoxic T lymphocytes (CTLs) may help treat difficult CMV infections. In earlier studies, these CTLs, which attack the virus, managed infections that resisted regular treatments. The treatment appears safe, with no major safety issues reported so far.

Donors provide these CTLs, which are then carefully prepared in labs to ensure safety and effectiveness. While more needs to be learned about long-term effects, current information suggests the treatment is safe for patients with complex CMV infections, especially those who have had transplants. The treatment is in the middle phase of trials, indicating it has been tested in humans before, but more research is needed to confirm all safety details. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for CMV infection rely on antiviral medications that inhibit viral replication. However, CMV-specific Cytotoxic T-Lymphocytes (CTLs) work differently by harnessing the body's immune system to target and destroy virus-infected cells. This personalized approach uses HLA-matched or mismatched donor cells, potentially offering a more precise attack on the virus. Researchers are excited about this treatment because it could offer a powerful option for patients with refractory CMV who don't respond to conventional antivirals, providing hope for more effective viral control.

What evidence suggests that Viral Specific Cytotoxic T-Lymphocytes might be an effective treatment for CMV infection?

This trial will evaluate the use of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) for patients with refractory CMV infection. Studies have shown that these special immune cells can help control difficult cases of CMV infection, particularly in patients who did not respond to regular treatments after transplants. CMV-CTLs target and destroy cells infected with the cytomegalovirus. Research indicates that this method can reduce the amount of virus in the body, even when other drugs do not work. Overall, using CMV-CTLs could be a promising way to tackle stubborn CMV infections. ^{1 2 3 4 5}

Who Is on the Research Team?

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Are You a Good Fit for This Trial?

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

Obtained informed consents by donor or donor legally authorized representative prior to donor collection

I have a family donor who matches me and is CMV positive or has a T-cell response to CMV.

Written informed consent given (by patient or legal representative) prior to any study-related procedures

Exclusion Criteria

I have been diagnosed with HIV.

Concomitant enrollment in another experimental clinical trial investigating the treatment of refractory CMV infection

Any medical condition which could compromise participation in the study according to the investigator's assessment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

CMV specific CTLs are administered to patients with refractory CMV infection

Up to 5 doses

1 visit per dose (in-person)

Follow-up

Participants are monitored for safety and effectiveness after each infusion

12 weeks after each infusion

Weekly monitoring (in-person or virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Viral Specific Cytotoxic T-Lymphocytes

Trial Overview 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.

How Is the Trial Designed?

Group I: Refractory CMV Experimental Treatment 1 Intervention

Patients with refractory CMV will be given one dose of CMV specific CTLs. HLA matched donors will get Dose 2.5 × 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:

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

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

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Medical College of Wisconsin

Collaborator

Trials

645

Recruited

1,180,000+

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

Washington University School of Medicine

Collaborator

Trials

2,027

Recruited

2,353,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Children's Hospital Los Angeles

Collaborator

Trials

257

Recruited

5,075,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

An innovative in vitro system was developed to generate human cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) using autologous donor leucocytes coated with CMV antigens, effectively producing CTLs from seropositive donors.

The study demonstrated that CMV-specific CTLs could be inhibited by monoclonal antibodies targeting CMV-related proteins, indicating a potential mechanism for regulating CTL activity in therapeutic settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definition of human cytomegalovirus-specific target antigens recognized by cytotoxic T cells generated in vitro by using an autologous lymphocyte system. Charpentier, B., Michelson, S., Martin, B.[2006]

Cytomegalovirus (CMV) reactivation poses significant risks for immunocompromised patients, such as those undergoing hematopoietic progenitor cell transplantation or living with HIV, leading to severe health complications despite antiviral treatments.

Recent advances in immunotherapy, including the adoptive transfer of CMV-specific T cell clones from seropositive donors, show promise in enhancing CMV-specific immunity and effectively treating CMV reactivation in these vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for cytomegalovirus (CMV) disease in immunocompromised patients. Lim, JB., Kwon, OH., Kim, HS., et al.[2005]

In a study of 18 patients after allogeneic hematopoietic stem cell transplantation, real-time polymerase chain reaction (RT-PCR) was found to be the most sensitive method for detecting CMV-specific T cells, identifying responses in 88% of cases when using a combination of pp65-peptide and pp65-protein for stimulation.

The use of pp65-protein for T-cell activation allows for detection of CMV-specific T cells without HLA restriction, enhancing the ability to monitor immune reconstitution and potentially guiding treatment strategies to prevent active CMV disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid monitoring of immune reconstitution after allogeneic stem cell transplantation--a comparison of different assays for the detection of cytomegalovirus-specific T cells. Abu-Khader, A., Krause, S.[2013]

In a study of 20 patients who received bone marrow transplants from CMV-seropositive donors, only half of the patients developed a detectable CMV-specific CTL response by 3 months post-transplant, indicating a delayed immune recovery.

Patients with an undetectable CMV-specific CTL response were at a significantly higher risk of developing severe CMV disease, including pneumonia, highlighting the importance of monitoring and potentially enhancing CTL responses in post-BMT care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Reusser, P., Riddell, SR., Meyers, JD., et al.[2021]

In a study of 3 CMV-seropositive patients who received stem cell transplants from CMV-seronegative donors, researchers found that CMV-specific CD8(+) T cells (CMV-CTLs) were predominantly mature effector cells, indicating a strong immune response post-transplant.

The study revealed that CMV-CTL clones persisted differently based on CMV reactivation; in one case without reactivation, recipient-derived CMV-CTLs dominated, while in cases with reactivation, the dominant clones were derived from the donor, highlighting the importance of donor-derived immunity in managing CMV after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence of recipient-derived as well as donor-derived clones of cytomegalovirus pp65-specific cytotoxic T cells long after allogeneic hematopoietic stem cell transplantation. Terasako-Saito, K., Nakasone, H., Tanaka, Y., et al.[2014]

In a study of 20 renal transplant recipients, CMV-specific cytotoxic T lymphocytes (CTLs) were found to limit the viral load of cytomegalovirus (CMV) as indicated by lower levels of antigenemia, suggesting their protective role against CMV disease.

The presence of CMV-specific CTLs was inversely correlated with high levels of antigenemia and the development of CMV disease, indicating that stronger CTL responses may help prevent severe CMV infections post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytomegalovirus (CMV)-specific T cell immunity after renal transplantation mediates protection from CMV disease by limiting the systemic virus load. Reusser, P., Cathomas, G., Attenhofer, R., et al.[2006]

The study demonstrates a rapid and efficient method for producing cytomegalovirus-specific cytotoxic T lymphocytes (CMV-CTLs) using the CliniMACS Prodigy device, taking approximately 13 hours, which is crucial for treating urgent CMV-related diseases after hematopoietic stem cell transplantation.

The produced CMV-CTLs showed a significant increase in functional activity, including effective proliferation and cytotoxicity against CMV-infected cells, indicating their potential as a safe and effective alternative to traditional antiviral drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Robust Production of Cytomegalovirus pp65-Specific T Cells Using a Fully Automated IFN-γ Cytokine Capture System. Kim, N., Nam, YS., Im, KI., et al.[2022]

The phase 2 study involved 50 recipients of allogeneic hematopoietic stem cell transplants who received donor-derived cytomegalovirus (CMV)-specific cytotoxic T cells, aiming to evaluate the efficacy of this treatment.

Outcomes were compared with a control group of patients who underwent the same transplant procedure but did not receive the CMV-specific CTLs, providing insights into the potential benefits of this immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy versus T lymphocytes for CMV. Heslop, HE.[2021]

CMV infection is a major risk after allogeneic stem cell transplantation, but reconstituting CMV-specific T cell responses can help protect patients from developing CMV disease.

Two strategies to enhance T cell immunity against CMV include transferring selected CMV-specific T cells directly from the donor to the patient and expanding these T cells in vitro using antigen presenting cells, both of which aim to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMV-specific T cell therapy. Einsele, H., Kapp, M., Grigoleit, GU.[2007]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8821006/

specific cytotoxic T lymphocyte therapy resolve CMV ... The use of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) has shown advantages in controlling refractory and late CMV infection when ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03266640

Study Details | NCT03266640 | Virus Specific Cytotoxic T- ... CMV specific CTLs will be collected from HLA matched or mismatched donors and manufactured in a GMP facility and administered to patients with refractory CMV ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9485495/

Donor-derived cytomegalovirus-cytotoxic T lymphocytes ... Several studies have shown that CMV-cytotoxic T lymphocytes (CTLs) can overcome drug-resistant CMV infection, but still many questions remain unanswered. Here, ...

4. ashpublications.org ashpublications.org/bloodadvances/article/5/2/496/474967/Adoptive-therapy-with-CMV-specific-cytotoxic-T

Adoptive therapy with CMV-specific cytotoxic T lymphocytes ... Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant.

5. academic.oup.com academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf232/8125789

Virus-Specific T-Cell Therapy for Prophylaxis and Treatment of ... Virus-specific T cells (VSTs) have been used for the prophylaxis and treatment of CMV infections. We conducted a scoping review to catalogue and characterize ...