Adoptive T Cell Therapy for Adenovirus Infections After Bone Marrow Transplant

Overseen By Mari H Dallas, MD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: Mari Dallas

Must not be taking: Antithymocyte globulin

Disqualifiers: Pregnancy, Breastfeeding, Opportunistic infections, GVHD, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called adoptive T cell therapy for adenovirus infections in patients who have undergone a bone marrow transplant. The goal is to determine if specialized immune cells from a donor can combat the virus and to identify any side effects. This trial may suit those who have received a bone marrow transplant, are struggling with adenovirus infections, and have not improved with standard antiviral treatments. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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 high doses of certain steroids or have had specific treatments like antithymocyte globulin recently, you may not be eligible to participate.

What prior data suggests that adoptive T cell therapy is safe for treating adenovirus infections after bone marrow transplant?

Research has shown that adoptive T cell therapy, which uses special T cells targeting adenovirus, is generally safe for patients. Previous studies used virus-specific donor T cells to help patients fight infections like those caused by adenovirus, and these studies found the treatment safe and effective.

However, since this therapy remains experimental and lacks FDA approval, researchers are focused on understanding its side effects and safety. The current trial is in its early stages, so the treatment's safety is still under evaluation, but early results are promising.

In summary, while adoptive T cell therapy shows potential, its safety is still under study. Participants should consider this when deciding to join a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for adenovirus infections after bone marrow transplants, which often involves antiviral medications and supportive care, adoptive T cell therapy uses virus-specific, antigen-selected T cells. This innovative treatment harnesses the body's immune system by infusing T cells that are specifically trained to target and destroy adenovirus-infected cells. Researchers are excited about this approach because it offers a targeted immune response, potentially leading to quicker and more effective clearance of the virus compared to traditional antiviral drugs. Additionally, this method could reduce reliance on broad-spectrum antivirals, which often come with significant side effects.

What evidence suggests that adoptive T cell therapy might be an effective treatment for adenovirus infections?

Research has shown that adoptive T cell therapy, which participants in this trial will receive, may help treat adenovirus infections in patients who have undergone a bone marrow transplant. Studies have found that these virus-specific T cells can strengthen the immune system by directly attacking infected cells. In past patients, these specially chosen T cells reduced the amount of virus in the body. Although early results are promising, this treatment remains experimental and is not yet approved by the FDA. The aim is to determine if these T cells can effectively fight the infection while minimizing side effects. ^{1 5 6 7 8}

Who Is on the Research Team?

Mari H Dallas, MD

Principal Investigator

University Hospitals, Seidman Cancer Center, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients who've had a bone marrow transplant at least 30 days ago and are struggling with adenovirus infections despite antiviral treatments, or can't tolerate such treatments. They should have an acceptable performance score indicating they're well enough to participate, be over 14 years old to consent, and use effective contraception.

Inclusion Criteria

I had a stem cell transplant from a donor and it's been over 30 days.

My condition did not improve with standard treatments or I cannot take them due to side effects.

- >1000 copies/ml in peripheral blood OR qualitative detection in stool, urine and/or other specimens

Exclusion Criteria

I am currently receiving high doses of steroids for severe graft versus host disease.

I haven't had virus-specific T cell treatment in the last 6 weeks.

I have a viral infection that is not human adenovirus (HAdV).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive virus-specific, antigen-selected T cells using the CliniMACS® Prodigy System

1 day

1 visit (in-person)

Observation

Participants are observed for safety and viral response after infusion

30 days

Regular monitoring

Follow-up

Participants are monitored for severe adverse events and clinical response

100 days

What Are the Treatments Tested in This Trial?

Interventions

• IFN-gamma-secreting HAdV antigen specific T cells

Trial Overview The study tests adoptive T cell therapy using donor immune cells (T cells) that fight the adenovirus. These T cells are infused into patients in hopes of boosting their ability to combat the infection. This experimental approach isn't FDA-approved yet.

How Is the Trial Designed?

Group I: Interferon (IFN)-gamma-secreting HAdV antigen specific T cells Experimental Treatment 1 Intervention

Virus-specific, antigen selected cells will be obtained using the CliniMACS® Prodigy System. The donor will be screened for their ability to produce an IFN-gamma- secretion response to HAdV by testing the donor's mononuclear cells with the Miltenyi Rapid Cytokine Inspector kit. Donors with appropriate IFN-gamma secretion response will undergo a steady state leukapheresis. The investigational product (IP) will be generated using the CCS-IFN enrichment program with an approximate duration time of 15 hours. IP will be suspended in 0.9 normal saline + 2.5% albumin and distributed for infusion and infused within 4 hours as a bolus on day 0. Subjects will receive virus-specific, antigen selected T cells within a targeted range of 1 x 10\^3- 2 x 10\^5 per kg of recipient weight.

Who Is Running the Clinical Trial?

Mari Dallas

Lead Sponsor

Trials

2

Recruited

40+

Published Research Related to This Trial

Transferring a specific T-cell receptor (TCR) into γ/δ T cells allows them to effectively target and kill adenovirus-infected cells, providing a promising immunotherapy option for patients after allogeneic hematopoietic stem cell transplantation (HSCT).

This approach not only enhances the immune response against adenovirus but also minimizes the risk of graft-versus-host disease (GvHD) since γ/δ T cells are not allo-reactive, making it a safer alternative compared to traditional α/β T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human adenovirus-specific γ/δ and CD8+ T cells generated by T-cell receptor transfection to treat adenovirus infection after allogeneic stem cell transplantation. Dörrie, J., Krug, C., Hofmann, C., et al.[2022]

Adenoviruses are common but usually not dangerous for healthy individuals; however, they can cause serious illness in immunocompromised patients, particularly children who have received stem cell transplants.

Adoptive T-cell immunotherapy shows promise as a treatment strategy for adenovirus infections in these high-risk patients, as the recovery of adenovirus-specific T cells is crucial for controlling the infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenoviral infections in hematopoietic stem cell transplantation. Leen, AM., Bollard, CM., Myers, GD., et al.[2014]

Adoptive transfer of naive CD8 T cells was ineffective in clearing influenza virus and promoting survival, highlighting the importance of using differentiated effector or memory T cells for effective immunotherapy.

Highly activated Tc1 effector cells showed rapid accumulation in the lungs and effectively reduced viral levels early in infection, suggesting that the stage of T cell differentiation is crucial for protective immunity against localized viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naive, effector, and memory CD8 T cells in protection against pulmonary influenza virus infection: homing properties rather than initial frequencies are crucial. Cerwenka, A., Morgan, TM., Dutton, RW.[2017]

A novel method was developed to generate adenovirus (ADV)-specific T cells from patients, which showed strong immune responses against both ADV species B and C, indicating potential for effective immunotherapy.

The study highlights that these T cells, primarily CD4(+) with an effector/memory profile, can be expanded and restimulated to target ADV infections, offering a promising strategy for patients, especially children, following hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capture and generation of adenovirus specific T cells for adoptive immunotherapy. Chatziandreou, I., Gilmour, KC., McNicol, AM., et al.[2017]

Adoptive transfer of virus-specific T cells from donors was successfully performed in nine children with systemic human adenovirus (HAdV) infection after stem cell transplantation, showing high specificity and reduced alloreactivity.

The treatment led to a successful immune response in five out of six evaluable patients, resulting in sustained expansion of HAdV-specific T cells and a significant reduction in viral copies, with the procedure being well tolerated overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Feuchtinger, T., Matthes-Martin, S., Richard, C., et al.[2006]

The study demonstrates a method to selectively expand and isolate functional HAdV-specific CD4+ T-cells from peripheral blood mononuclear cells (PBMCs) using artificial antigen-presenting cells, which is crucial for developing targeted therapies against HAdV infections in pediatric patients after stem cell transplantation.

These HAdV-specific T-cells effectively kill HAdV-infected cells and produce pro-inflammatory cytokines without showing alloreactivity, indicating their potential for safe and effective adoptive transfer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selection of perforin expressing CD4+ adenovirus-specific T-cells with artificial antigen presenting cells. Haveman, LM., Bierings, M., Klein, MR., et al.[2013]

Adoptive transfer of hexon-specific T cells, generated from donor mononuclear cells, shows promise as a treatment for adenovirus infections in patients post-hematopoietic stem cell transplantation, with over 72% of donors demonstrating a sufficient T-cell response.

The generated T cells exhibit strong cytotoxicity against adenovirus and good crossreactivity with different viral strains, indicating their potential effectiveness in restoring T-cell immunity against adenovirus infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical grade generation of hexon-specific T cells for adoptive T-cell transfer as a treatment of adenovirus infection after allogeneic stem cell transplantation. Feuchtinger, T., Richard, C., Joachim, S., et al.[2020]

Human CD4(+) T cells, specifically IL-12-polarized Th1 cells, can directly influence viral clearance by secreting proinflammatory cytokines like IFN-gamma and TNF-alpha, which have potent antiviral effects against various viruses.

These cytokines not only inhibit hepatitis C virus replication directly but also exert antiviral effects against vesicular stomatitis virus indirectly through the type I IFN receptor, demonstrating the dual role of CD4(+) T cells in regulating antiviral responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blockade of virus infection by human CD4+ T cells via a cytokine relay network. Davis, AM., Hagan, KA., Matthews, LA., et al.[2021]

The study found that tetanus toxoid (TT) vaccination induces a strong and consistent immune response, specifically increasing the number of TT-specific CD4+ T cells that secrete Interferon-gamma (IFN-gamma) in healthy individuals over a period of more than two years.

Booster immunizations with TT significantly enhanced the number of these specific T cells, peaking at four weeks post-vaccination, demonstrating the efficacy of TT in eliciting a robust immune response mediated by HLA class-II restricted CD4+ T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay. Mayer, S., Laumer, M., Mackensen, A., et al.[2008]

Therapeutic antiviral T cells can effectively eliminate the lymphocytic choriomeningitis virus (LCMV) from the brain of persistently infected mice without causing damage to the blood-brain barrier or surrounding tissue, highlighting a safe approach to treating neurotropic infections.

The mechanism involves a tailored release of chemoattractants that recruit T cells while minimizing harmful innate immune responses, and the T cells interact with brain-resident microglia to enhance their role as antigen-presenting cells, facilitating a noncytopathic clearance of the virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells. Herz, J., Johnson, KR., McGavern, DB.[2023]

Long-lived virus-specific memory T cells can be effectively generated from purified effector T cells that secrete cytokines, such as interferon gamma and interleukins, indicating a successful pathway for developing memory T cells.

This study supports the linear differentiation model of memory T cell development, suggesting that vaccines and immune therapies should focus on utilizing differentiated effector T cells to enhance immune responses against viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. Löhning, M., Hegazy, AN., Pinschewer, DD., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03378102?tab=results

Antigen Specific Adoptive T Cell Therapy for Adenovirus ... Antigen Specific Adoptive T Cell Therapy for Adenovirus Infection After Hematopoietic Stem Cell Transplantation. ClinicalTrials.gov ID ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12116135/

Treating Adenovirus Infection in Transplant Populations Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0966327424001096

Immune reconstitution and cidofovir administration rescue ... We report a patient with disseminated HAdV infection successfully treated with cidofovir, and investigated the immune reconstitution and anti-HAdV specific ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT03378102/antigen-specific-adoptive-t-cell-therapy-for-adenovirus-infection-after-hematopoietic-stem-cell-transplantation

Antigen Specific Adoptive T Cell Therapy for Adenovirus ... The purpose of this study is to determine if it is possible to treat an infection with a cell-based immunotherapy (therapy that uses the ...

5. withpower.com withpower.com/trial/early-phase-1-adenoviridae-infections-2019-f79aa

Adoptive T Cell Therapy for Adenovirus Infections After ... This Phase < 1 medical study run by Mari Dallas is evaluating whether IFN-gamma-secreting HAdV antigen specific T cells will have tolerable side effects ...

6. clinicaltrial.be clinicaltrial.be/en/details/189995?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Antigen Specific Adoptive T Cell Therapy for Adenovirus I... To describe the safety profile of the infusion of virus - specific, antigen selected T cells. To describe the toxicities related to infusion of ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16803570/

Safe adoptive transfer of virus-specific T-cell immunity for ... We present feasibility data for a new treatment option using virus-specific donor T cells for adoptive transfer of immunity to patients with HAdV-infection/ ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723011727

Adenoviral Penton and Hexon Proteins Are Equivalent ... Our study demonstrates that penton is an important immunodominant target antigen of HAdV reactivation/ infection after HSCT in most patients.