Cytotoxic T-Lymphocytes for Adenovirus Infections

Recruiting at 10 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

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 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for adenovirus infections in children and young adults who have struggled after stem cell or organ transplants. The treatment uses special immune cells, called adenovirus-specific cytotoxic T-lymphocytes, to target and fight the adenovirus. Suitable candidates have adenovirus infections that did not improve with standard antiviral treatments and show symptoms like lung, bladder, colon, or liver issues. Participants must have a related donor whose immune cells can respond to the virus. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on steroids at a dose higher than 0.5 mg/kg prednisone equivalent, you may not be eligible to participate.

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

Research has shown that a special type of immune cell treatment is safe for treating difficult adenovirus infections. These immune cells, called CTLs, are taken from a donor and help fight the virus in patients who have had stem cell or organ transplants. The treatment was tested on patients with weakened immune systems and was generally well-tolerated. Studies have not found major safety concerns, indicating that this treatment can be safely used in those who need it most. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for adenovirus infections focus on managing symptoms and supporting the immune system, often relying on antiviral drugs like cidofovir. However, adenovirus-specific cytotoxic T-lymphocytes (CTLs) offer a novel approach by directly targeting and eliminating infected cells. Researchers are excited about this because CTLs harness the body's own immune response, potentially leading to more effective and quicker resolution of the infection. Unlike traditional antivirals, which can have limited effectiveness and side effects, CTLs are designed to specifically target the adenovirus, offering a more precise and potentially safer treatment option.

What evidence suggests that Adenovirus-specific Cytotoxic T-lymphocytes might be an effective treatment for adenovirus infections?

Research has shown that special immune cells, called adenovirus-specific T-cells, can help treat difficult adenovirus infections, especially in people who have had stem cell transplants. In this trial, participants with adenoviral infection will receive adenovirus-specific cytotoxic T-lymphocytes (CTLs) to evaluate their effectiveness. Early results from previous studies indicate that these T-cells are safe and beneficial for patients who haven't improved with standard treatments. Studies have found that these T-cells can help the body fight the virus, which is crucial for those with weakened immune systems due to transplants. This method has successfully treated adenovirus infections in children and young adults, providing hope when regular antiviral medications don't work well. Overall, using these virus-targeted T-cells can significantly strengthen the immune system, helping to combat persistent infections. ^{2 3 4 5 6}

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 (0.1-30 years old) with stubborn adenovirus infections after a stem cell or organ transplant, or those with primary immunodeficiencies. They must have tried antiviral treatments without success and be in relatively stable condition. A related donor who matches the patient's tissue type and can respond to the virus is also needed.

Inclusion Criteria

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

You have experienced negative reactions or side effects from antiviral treatments in the past.

My kidney function is reduced due to cidofovir treatment.

Exclusion Criteria

I am HIV positive.

I am not pregnant, breastfeeding, and I agree to use birth control during the study.

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

Participants receive ADV-specific cytotoxic T cells intravenously. Patients may receive up to 5 infusions if they do not respond to the first infusion.

12 weeks

Weekly monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and response to treatment.

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Adenovirus-specific Cytotoxic T-lymphocytes

Trial Overview The study tests if special immune cells called cytotoxic T-lymphocytes from a related donor can fight off tough adenovirus infections when standard antiviral drugs fail. These cells are given through an IV and are designed to target the virus directly.

How Is the Trial Designed?

Group I: patients with adenoviral infection Experimental Treatment 1 Intervention

patients will receive CTL dose x 1 with 2.5 × 10(4) CD3/kg for matched related donor and 0.5 × 104 CD3/kg for mis-matched related donor. Patients who don't respond to the first infusion may receive up to a total 5 CTL infusions.

Adenovirus-specific Cytotoxic T-lymphocytes is already approved in United States for the following indications:

Approved in United States as Adenovirus-specific CTLs for:

• Refractory adenovirus 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+

Washington University School of Medicine

Collaborator

Trials

2,027

Recruited

2,353,000+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Medical College of Wisconsin

Collaborator

Trials

645

Recruited

1,180,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

University of Colorado, Denver

Collaborator

Trials

1,842

Recruited

3,028,000+

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Published Research Related to This Trial

In a study of 21 children with adenovirus (ADV) infection post-allogeneic stem cell transplantation (SCT), those who survived had detectable ADV-specific T cells, while all patients who experienced ADV-associated mortality lacked these protective T cells.

Children who successfully cleared ADV infection had significantly higher levels of ADV-specific T cells compared to those who did not get infected, suggesting that the presence of these T cells is crucial for protection against severe ADV infections after SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of adenovirus-specific T cells in children with adenovirus infection after allogeneic stem cell transplantation. Feuchtinger, T., Lücke, J., Hamprecht, K., et al.[2008]

Researchers identified 5 new CD8(+) T-cell epitopes from the adenovirus hexon protein, which are crucial for developing targeted T-cell therapies against adenovirus infections in immunocompromised patients.

The study found that T cells could cross-react with multiple adenovirus groups, suggesting that a T-cell population can be engineered to effectively target a wide range of adenoviruses, enhancing treatment options for vulnerable individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells. Leen, AM., Sili, U., Vanin, EF., et al.[2021]

A new in vitro system was developed to generate cytotoxic T cells (CTLs) that effectively respond to adenovirus infections, which is crucial for understanding immune responses in immunocompromised patients.

The study found that CTLs can recognize and kill cells infected with different subgroups of adenoviruses, suggesting that there are common viral epitopes, which could help in designing broader therapeutic strategies against adenovirus infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-pulsed dendritic cells stimulate human virus-specific T-cell responses in vitro. Smith, CA., Woodruff, LS., Kitchingman, GR., et al.[2020]

A clinical-grade method was developed to isolate and expand adenovirus-specific T cells from donors, yielding an average of 3.4 million specific T lymphocytes from peripheral blood or leukapheresis products, which is crucial for restoring immunity in patients with lymphopenia after stem cell transplantation.

The generated T cell lines demonstrated effective responses against adenovirus-infected cells and showed reduced alloreactive proliferation, indicating their potential for safe and effective adoptive immunotherapy in combating ADV infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolation and expansion of human adenovirus-specific CD4+ and CD8+ T cells according to IFN-gamma secretion for adjuvant immunotherapy. Feuchtinger, T., Lang, P., Hamprecht, K., et al.[2019]

The study identified 33 new CD4(+) and CD8(+) T-cell epitopes from the adenoviral hexon protein, which is crucial for developing targeted therapies against adenoviral infections in immunocompromised patients.

Most of these newly identified epitopes are shared among different adenovirus subspecies, indicating that T cells targeting these epitopes could provide broad protection against multiple adenovirus serotypes, enhancing the potential for effective adoptive T-cell transfer or vaccine strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of hexon-specific CD4 and CD8 T-cell epitopes for vaccine and immunotherapy. Leen, AM., Christin, A., Khalil, M., et al.[2021]

Adenoviruses are common but usually not dangerous for healthy individuals, while they can cause serious illness in immunocompromised patients, highlighting the need for effective treatments in these vulnerable groups.

The study suggests that using in vitro expanded virus-specific cytotoxic T lymphocytes (CTLs) could be a promising approach for treating or preventing adenovirus infections in immunosuppressed patients, as these T cells play a crucial role in controlling the virus in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell immunotherapy for adenoviral infections of stem-cell transplant recipients. Leen, AM., Myers, GD., Bollard, CM., et al.[2007]

Cytotoxic T lymphocytes (CTLs) can be effectively generated from spleen cells of reovirus-infected mice when stimulated with reovirus-infected cells, demonstrating a targeted immune response.

The specificity of these CTLs is linked to the SI gene of the reovirus, which encodes the viral hemagglutinin and influences how the virus infects cells, particularly in the nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of cytolytic T lymphocytes after reovirus infection: role of S1 gene. Finberg, R., Weiner, HL., Fields, BN., et al.[2019]

Adenovirus can trigger specific cytotoxic T-lymphocyte (CTL) responses in humans, which can destroy transduced cells, posing a challenge for its use as a gene therapy vector.

The study found that the E3-19K protein in adenovirus-infected cells hinders CTL recognition, but treatment with gamma interferon can enhance the visibility of these cells to the immune system, potentially improving the effectiveness of adenovirus-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human adenovirus-specific CD8+ T-cell responses are not inhibited by E3-19K in the presence of gamma interferon. Flomenberg, P., Piaskowski, V., Truitt, RL., et al.[2020]

Citations

1. astctjournal.org astctjournal.org/article/S2666-6367(23)02356-4/fulltext

Specific Cytotoxic T-Lymphocytes (CTLs) for Resistant ... Preliminary data affirm that donor ADV-specific CTLs are safe and effective in treating refractory ADV cases post-AlloHSCT.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03266627?cond=%22Adenoviridae%20Infections%22&aggFilters=status:not%20rec&rank=4

specific Cytotoxic T-lymphocytes for Refractory Adenovirus ... Related donor Adenovirus (ADV) specific cytotoxic T cells (CTLs) manufactured with the Miltenyi CliniMACS Prodigy Cytokine Capture System will be administered ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8525242/

Virus-specific T cells for adenovirus infection after stem ... VSTs are effective in treating adenoviral infections, a common posttransplant complication in pediatrics that lacks effective antivirals.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123114376

Treatment of Refractory Adenovirus (ADV) Infections Using ... The use of virus-specific (vs) CTLs in immunocompromised patients offer an opportunity to restore temporary virus specific immunity. From the Viral Cytotoxic T- ...

5. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/4836/505411/Treatment-of-Refractory-Adenovirus-ADV-Infections

Treatment of Refractory Adenovirus (ADV) Infections Using ... Treatment of refractory adenovirus (ADV) infections using Adv-specific cytotoxic T-lymphocytes (CTLs) in children, adolescents and young adults (CAYA)

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03266627

Adenovirus-specific Cytotoxic T-lymphocytes for Refractory ... adenovirus specific cytotoxic t-lymphocytes will be collected and manufactured from HLA matched related or HLA mis-matched related donors and administered to ...