CMV-Specific CTLs for CMV Infection

Recruiting at 8 trial locations

Overseen by Mitchell S Cairo, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: New York Medical College

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

Disqualifiers: Acute GVHD, Poor performance, HIV, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

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

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.

What data supports the effectiveness of the treatment CMV-specific CTLs for CMV infection?

Research shows that CMV-specific cytotoxic T cells (CTLs) can help control CMV infection after stem cell and bone marrow transplants by reducing the risk of severe CMV disease. Patients with a strong CMV-specific CTL response were less likely to develop CMV-related complications, suggesting that this treatment can be effective in managing CMV infections. ^{1 2 3 4 5}

Is CMV-specific CTL treatment safe for humans?

CMV-specific cytotoxic T lymphocytes (CTLs) have been reported to provide long-term immunity against CMV without major side effects, making them a generally safe alternative to antiviral drugs for patients who have undergone stem cell transplantation. ^{1 6 7 8 9}

How is the CMV-specific CTL treatment different from other treatments for CMV infection?

The CMV-specific CTL treatment is unique because it uses the patient's own immune cells, which are trained to specifically target and destroy CMV-infected cells, offering a personalized approach that can be more effective in reconstituting immunity in immunocompromised patients compared to standard antiviral drugs. ^{1 2 4 5 6}

Research Team

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

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

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.

I am between the ages of 0 and 79.

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

Trial Timeline

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)

Treatment Details

Interventions

• Viral Specific Cytotoxic T-Lymphocytes (Virus Therapy)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Edward C. Halperin

New York Medical College

Chancellor and Chief Executive Officer since 2012

B.S. in Economics, Summa Cum Laude, The Wharton School, University of Pennsylvania; M.A., Liberal Studies, Duke University; M.D., Cum Laude, Yale University

Machelle Allen

New York Medical College

Chief Medical Officer since 2017

MD from New York Medical College

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Joseph W. St. Geme III

Children's Hospital of Philadelphia

Chief Medical Officer since 2021

MD, PhD, MPH

Madeline Bell

Children's Hospital of Philadelphia

Chief Executive Officer since 2015

BSc in Nursing from Villanova University, MSc in Organizational Dynamics from the University of Pennsylvania

Medical College of Wisconsin

Collaborator

Trials

645

Recruited

1,180,000+

Dr. Joseph E. Kerschner

Medical College of Wisconsin

Chief Medical Officer since 2011

MD, specific institution not identified

Dr. John R. Raymond, Sr.

Medical College of Wisconsin

Chief Executive Officer since 2010

MD from the Medical University of South Carolina

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

Alan Palkowitz

Indiana University

Chief Executive Officer since 2020

PhD in Chemistry from Indiana University

David Ingram

Indiana University

Chief Medical Officer since 2020

MD from Indiana University School of Medicine

Washington University School of Medicine

Collaborator

Trials

2,027

Recruited

2,353,000+

David H. Perlmutter

Washington University School of Medicine

Chief Executive Officer since 2015

MD from Washington University School of Medicine

Paul Scheel

Washington University School of Medicine

Chief Medical Officer since 2022

MD from Washington University School of Medicine

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Theodore DeWeese

Johns Hopkins University

Chief Executive Officer since 2023

MD from an unspecified institution

Allen Kachalia

Johns Hopkins University

Chief Medical Officer since 2023

MD from an unspecified institution

Children's Hospital Los Angeles

Collaborator

Trials

257

Recruited

5,075,000+

Paul S. Viviano

Children's Hospital Los Angeles

Chief Executive Officer since 2015

Master of Public Health from UCLA Fielding School of Public Health

Alan S. Wayne

Children's Hospital Los Angeles

Chief Medical Officer since 2023

MD

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Catherine Krawczeski

Nationwide Children's Hospital

Chief Medical Officer

MD

Timothy C. Robinson

Nationwide Children's Hospital

Chief Executive Officer since 2019

BSc in Psychology and Business Administration from Indiana University

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Suresh Gunasekaran

University of California, San Francisco

Chief Executive Officer since 2022

MBA from Southern Methodist University

Dr. Lukejohn Day

University of California, San Francisco

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2013]

2. United States 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. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

CMV-specific T cell therapy. [2007]

4. United States 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. [2006]

5. United States 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. [2006]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for cytomegalovirus (CMV) disease in immunocompromised patients. [2005]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Robust Production of Cytomegalovirus pp65-Specific T Cells Using a Fully Automated IFN-γ Cytokine Capture System. [2022]

8. Denmark 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. [2014]

9. United States pubmed.ncbi.nlm.nih.gov

Pharmacotherapy versus T lymphocytes for CMV. [2021]