Cytotoxic T-Lymphocytes for Adenovirus Infections

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

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

Trial Summary

What is the purpose of this trial?

Related donor Adenovirus (ADV) specific cytotoxic T cells (CTLs) manufactured with the Miltenyi CliniMACS Prodigy Cytokine Capture System will be administered intravenously in in children, adolescents and young adults with refractory ADV infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), with primary immunodeficiencies (PID) or post solid organ transplant. Funding Source: FDA OOPD

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.

What data supports the effectiveness of the treatment Adenovirus-specific Cytotoxic T-lymphocytes for adenovirus infections?

Research shows that having specific T cells (a type of immune cell) is important for fighting adenovirus infections, especially in people with weakened immune systems. Studies have found that patients who have more of these specific T cells are better able to clear the infection, suggesting that using these T cells as a treatment could help control adenovirus infections. ^{1 2 3 4 5}

Is the use of cytotoxic T-lymphocytes for adenovirus infections safe in humans?

Research suggests that using cytotoxic T-lymphocytes (CTLs) to treat adenovirus infections is generally safe, especially in immunocompromised patients, as these CTLs are derived from healthy donors and are designed to target the virus specifically. However, the safety data primarily comes from studies involving patients with weakened immune systems, such as those who have undergone stem cell transplants. ^{1 3 4 5 6}

How is the treatment Adenovirus-specific Cytotoxic T-lymphocytes different from other treatments for adenovirus infections?

Adenovirus-specific Cytotoxic T-lymphocytes (CTLs) are unique because they use immune cells specifically trained to target and destroy adenovirus-infected cells, offering a targeted approach for immunocompromised patients where traditional antiviral drugs may not be effective. This treatment leverages the body's own immune response by expanding virus-specific T cells in the lab and then reintroducing them to the patient, providing a tailored immune boost against the virus. ^{1 3 5 7 8}

Research Team

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Adenovirus-pulsed dendritic cells stimulate human virus-specific T-cell responses in vitro. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Detection of adenovirus-specific T cells in children with adenovirus infection after allogeneic stem cell transplantation. [2008]

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

T-cell immunotherapy for adenoviral infections of stem-cell transplant recipients. [2007]

4. Netherlands 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. [2019]

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

Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells. [2021]

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

Human adenovirus-specific CD8+ T-cell responses are not inhibited by E3-19K in the presence of gamma interferon. [2020]

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

Identification of hexon-specific CD4 and CD8 T-cell epitopes for vaccine and immunotherapy. [2021]

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

Generation of cytolytic T lymphocytes after reovirus infection: role of S1 gene. [2019]