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?

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 patient's own immune system to treat the infection). This treatment is called adoptive T cell therapy. Another purpose is to learn about the side effects and toxicities of adoptive T cell therapy. Adoptive T cell therapy is an investigational (experimental) therapy that works by using the blood of a donor that has immunity against the virus. The donor cells are collected and then the cells, called T cells, that are capable of defending against the virus are selected out. These selected T cells are then infused back into the patient, to try to give the immune system the ability to fight the infection. Adoptive T cell therapy is experimental because it is not approved by the Food and Drug Administration (FDA).

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.

Is adoptive T cell therapy generally safe for humans?

Adoptive T cell therapy has been used in clinical studies for treating various viral infections, including adenovirus, and has shown promise without causing significant tissue damage or harmful immune reactions in the central nervous system. ^{1 2 3 4 5}

How is the treatment for adenovirus infections after bone marrow transplant unique?

This treatment uses specially prepared T cells from donors to help the patient's immune system fight adenovirus infections, which is different from standard antiviral drugs that often don't work well. The T cells are selected for their ability to target the virus specifically, making this a novel approach for patients with weakened immune systems after a bone marrow transplant. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment for adenovirus infections after bone marrow transplant?

Research shows that using virus-specific T cells, which are immune cells trained to target adenovirus, can help clear the virus in patients who have had a bone marrow transplant. In several studies, patients receiving these T cells showed a reduction in viral levels and improved recovery, indicating that this treatment can be effective in managing adenovirus infections. ^{6 8 9 10 11}

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. United States 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. [2022]

2. England 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. [2006]

3. United States 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. [2020]

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

Selection of perforin expressing CD4+ adenovirus-specific T-cells with artificial antigen presenting cells. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Capture and generation of adenovirus specific T cells for adoptive immunotherapy. [2017]

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

Blockade of virus infection by human CD4+ T cells via a cytokine relay network. [2021]

7. United States 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. [2017]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay. [2008]

9. United States 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. [2022]

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

Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells. [2023]

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

Adenoviral infections in hematopoietic stem cell transplantation. [2014]