Adoptive Immunotherapy for Viral Infections

Recruiting at 2 trial locations

Overseen By Allistair Abraham, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Catherine Bollard

Disqualifiers: Pregnant, CNS disease, Myelofibrosis, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 45 days

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment using special immune cells, known as CMV/AdV/EBV/BKV specific T cells, to combat viral infections like CMV, EBV, BKV, and Adenovirus in transplant patients. The goal is to determine the optimal dose of these immune cells to safely and effectively help the body fight these viruses. Individuals who have undergone a cord blood transplant and are at risk for or dealing with these specific viral infections might be suitable candidates for the trial. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical advancements.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are unable to reduce steroids to a certain level or if you have received an investigational product recently.

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

Research has shown that virus-specific T cells, a type of immune cell, can safely and effectively treat viral infections such as CMV, EBV, BKV, and Adenovirus. Studies have found that patients usually tolerate these treatments well. For instance, trials with T cells targeting CMV and EBV confirmed their safety in both preventing and treating these infections. Another study noted that patients using T-cell therapies for similar viruses did not experience serious safety issues. This suggests that targeting multiple viruses with T cells might be safe for prospective trial participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about these treatments because they use virus-specific T cells to target infections like CMV, AdV, EBV, and BKV in a precise way. Unlike standard antiviral drugs that can have broad effects and potential side effects, these T cells are designed to directly target and attack the cells infected with the virus. This approach not only promises a more focused treatment but could also reduce the risk of damage to healthy cells and improve patient outcomes. Additionally, the unique delivery method—administering cells through a quick intravenous injection—can streamline the treatment process, potentially leading to faster results.

What evidence suggests that CMV/AdV/EBV/BKV specific T cells might be an effective treatment for viral infections?

Research has shown that virus-specific T cells offer a promising approach to treating viral infections such as CMV, EBV, BKV, and Adenovirus. These T cells, a type of white blood cell, target specific viruses, aiding in the control and treatment of infections in individuals with weakened immune systems. Studies have found this method effective in managing issues caused by these viruses, particularly when standard antiviral treatments fail. In this trial, participants will receive CMV/AdV/EBV/BKV-specific T cells, which have successfully treated conditions related to EBV and complications from Adenovirus. Early results suggest this treatment could provide a new way to combat these challenging viral infections. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for pediatric and adult patients with malignant or nonmalignant diseases who are candidates for a cord blood transplant. They must have a certain level of physical function, no severe organ damage, and be at least 30 days post-transplant without significant graft-versus-host disease. It's not for pregnant women, those with very low performance status, uncontrolled infections other than the viruses in question, or those who've received another investigational product within 28 days.

Inclusion Criteria

I am more than 30 days post-transplant.

Written informed consent and/or signed assent line from patient, parent or guardian

I can care for myself but may need occasional help.

Exclusion Criteria

I am on high levels of oxygen therapy.

My transplant is not fully matching or my original disease has returned.

I cannot reduce my steroid dose to less than or equal to 0.5 mg/kg/day.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of CMV/AdV/EBV/BKV-specific CTLs with dose escalation based on toxicity and efficacy

45 days

1 visit (in-person) for infusion, followed by monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including toxicity and immune reconstitution

12 months

Regular visits for monitoring (frequency not specified)

Optional Additional Doses

Participants with partial response or affected CTL function may receive up to 2 additional doses 28 days after the first infusion

28 days after initial treatment

What Are the Treatments Tested in This Trial?

Interventions

• CMV/AdV /EBV/BKV specific T cells

Trial Overview

The trial tests different doses of donor-derived T cells that fight CMV, EBV, BKV and Adenovirus in patients receiving cord blood transplants. Up to 36 patients will receive one of three escalating dose levels determined by an adaptive method to find the optimal balance between effectiveness and toxicity.

How Is the Trial Designed?

Group I: CMV/AdV /EBV/BKV specific T cells Experimental Treatment 1 Intervention

CMV/AdV /EBV/BKV specific T cells will be thawed and transferred to a syringe given by slow intravenous injection over 1-2 minutes. Three dose levels will be explored. The lowest dose level will be 1x107cells/m2 and the highest will be 5x107/m2.

CMV/AdV /EBV/BKV specific T cells is already approved in United States, European Union for the following indications:

Approved in United States as CMV/AdV/EBV/BKV specific T cells for:

• Treatment of persistent or relapsed CMV disease or infection
• Treatment of persistent adenovirus infection or disease
• Treatment of persistent EBV infection
• Treatment of persistent BK virus infection or BK virus disease

Approved in European Union as CMV/AdV/EBV/BKV specific T cells for:

• Treatment of persistent or relapsed CMV disease or infection
• Treatment of persistent adenovirus infection or disease
• Treatment of persistent EBV infection
• Treatment of persistent BK virus infection or BK virus disease

Who Is Running the Clinical Trial?

Catherine Bollard

Lead Sponsor

Trials

13

Recruited

290+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 17 hematopoietic stem cell transplant recipients with BKV-related cystitis, 71% showed specific T-cell responses to the BK virus, indicating a strong immune reaction.

Virus-specific T cell (VST) therapy was effective, with 6 out of 7 patients treated showing specific T-cell responses, suggesting that VSTs may enhance the immune response against BKV compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Follow-Up after Adoptive Transfer of BK-Virus-Specific T Cells in Hematopoietic Stem Cell Transplant Recipients. Koldehoff, M., Eiz-Vesper, B., Maecker-Kolhoff, B., et al.[2023]

Cytomegalovirus (CMV) and BK virus (BKV) are significant threats to kidney transplant patients, negatively impacting both short- and long-term graft survival despite advances in screening and prophylaxis.

Adoptive T cell transfer, which involves infusing virus-specific T lymphocytes, shows promise as a safe and effective immunotherapy to restore T cell immunity against CMV and BKV, suggesting it could enhance antiviral treatment strategies for kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Virus-Specific T Cell Therapy for Cytomegalovirus and BK Infections in Kidney Transplant Recipients. Parajuli, S., Jorgenson, M., Meyers, RO., et al.[2023]

The study demonstrated the successful generation of virus-specific T cells (VSTs) that target 12 antigens from five different viruses, showing promise for treating infections in immunocompromised patients.

In a clinical trial involving 11 allogeneic transplant recipients, the VSTs were safe and resulted in a remarkable 94% response rate in managing active viral infections, with effects sustained over the long term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Papadopoulou, A., Gerdemann, U., Katari, UL., et al.[2022]

A new method allows for the rapid generation of virus-specific T cells targeting EBV, CMV, and adenovirus in just 2-3 weeks without using infectious viruses, making the process simpler and more accessible.

In a study involving 12 transplant recipients with active viral infections, 80% achieved complete virological responses, with no immediate or delayed toxicities observed, indicating both safety and efficacy of this T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant. Gerdemann, U., Katari, UL., Papadopoulou, A., et al.[2022]

In a study of 23 kidney transplant recipients with viral infections (ADV, BKV, CMV), virus-specific T cell therapy (VSTs) led to complete resolution of ADV infections after just one infusion.

While VSTs showed a moderate effect on BKV and CMV infections, with nearly a 50% reduction in viral load, some patients experienced complications like chronic allograft nephropathy and acute rejection, highlighting the need for further research on the safety and efficacy of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viral specific T cell therapy in kidney transplant recipients - A single-center experience. Anand, M., Nysather, J., McGraw, G., et al.[2023]

The study identifies a method to effectively capture and expand BKV-specific CD4(+) T cells from kidney transplant patients, which is crucial for improving immune responses against BK virus reactivation.

BKV-specific CD4(+) T cells were found to be multifunctional and cytolytic, indicating their significant role in controlling BKV replication, thus highlighting their potential for use in adoptive immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of CD4(+) T cells in BKV-specific T cell immunity. Weist, BJ., Schmueck, M., Fuehrer, H., et al.[2021]

Adoptive immunotherapy using virus-specific T lymphocytes can effectively restore immunity against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (ADV) without causing acute toxicity or increasing the risk of graft-versus-host disease, making it a safe treatment option.

In a study of 204 healthy donors, significant variations in T cell frequencies were found, with 100% of CMV-seropositive donors showing specific T cells, indicating that targeting specific antigens like CMVpp65 and EBVBZLF1 could enhance the efficacy of immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMV-, EBV- and ADV-specific T cell immunity: screening and monitoring of potential third-party donors to improve post-transplantation outcome. Sukdolak, C., Tischer, S., Dieks, D., et al.[2013]

Adoptive transfer of virus-specific T cells (VSTs) can effectively prevent or treat infections caused by latent viruses like CMV, EBV, and ADV in immunocompromised patients, improving clinical outcomes.

Recent advancements in T cell manufacturing and isolation techniques, such as using G-Rex flasks and major histocompatibility complex tetramers, enable quicker and safer production of VSTs, potentially making these therapies more accessible and cost-effective for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoring antiviral immunity with adoptive transfer of ex-vivo generated T cells. Migliori, E., Chang, M., Muranski, P.[2023]

In a phase II clinical trial involving 38 patients, the use of banked virus-specific T cells (VSTs) showed a remarkable 92% overall response rate in treating severe viral infections after hematopoietic stem-cell transplantation, with complete responses for BKV and EBV infections.

The treatment was safe, with only two mild cases of graft-versus-host disease reported, and the VSTs demonstrated persistence for up to 12 weeks, providing broad antiviral protection against multiple viral pathogens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation. Tzannou, I., Papadopoulou, A., Naik, S., et al.[2022]

The study successfully isolated and expanded cytomegalovirus-specific CD8+ T cell clones from bone marrow donors, demonstrating the feasibility of using adoptive T cell transfer for human therapy.

After transferring these T cell clones to immunodeficient bone marrow transplant recipients, there was no observed toxicity, and the T cells provided a lasting immune response against cytomegalovirus, indicating their potential effectiveness in treating viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Riddell, SR., Watanabe, KS., Goodrich, JM., et al.[2023]

BKV-specific CD8(+) T cells are present in low frequencies in healthy individuals and have a unique memory phenotype, which suggests they may play a role in controlling BK virus reactivation in immunocompromised patients.

These T cells exhibit limited direct cytotoxic capacity but are polyfunctional, capable of producing key cytokines like IL-2 and IFN-γ, indicating their potential importance in antiviral immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic and functional characterization of circulating polyomavirus BK VP1-specific CD8+ T cells in healthy adults. van Aalderen, MC., Remmerswaal, EB., Heutinck, KM., et al.[2021]

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