Adoptive Immunotherapy for Viral Infections

Recruiting at 1 trial location

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 Phase I-II dose-finding trial to determine the optimal dose of intravenous (IV) injection dose of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV, EBV, BKV and Adenovirus. A maximum of 36 patients will be treated in up to 18 cohorts each of size 2, with the first cohort treated at the lowest dose level 1, all successive doses chosen by the EffTox method, and no untried dose level skipped when escalating. The scientific goal of the trial is to determine an optimal IV-CTL cell dose level among the three doses 1.0x107cells/m2, 2 x107cells/m2 and 5x107cells/m2., hereafter dose levels 1, 2, 3. Dose-finding will be done using the sequentially adaptive EffTox trade-off-based design of Thall et al.

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 adoptive immunotherapy with virus-specific T cells safe for humans?

Adoptive immunotherapy using virus-specific T cells (VSTs) has been shown to be safe in humans, with studies reporting minimal side effects such as mild graft-versus-host disease in a few cases. These treatments have been used successfully in patients with viral infections after stem cell transplants, showing that they can be a safe option for managing severe viral infections. ^{1 2 3 4 5}

How is the treatment with virus-specific T cells different from other treatments for viral infections?

This treatment uses virus-specific T cells (VSTs) to boost the immune system's ability to fight viral infections, which is different from traditional antiviral drugs that directly target the virus. The VSTs are generated quickly without using live viruses, making them safer and more accessible for patients with weakened immune systems. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment for viral infections?

Research shows that virus-specific T cells (VSTs) can effectively treat severe viral infections after stem cell transplants, with a high response rate for viruses like BK virus and cytomegalovirus. In a study, 92% of patients showed improvement, indicating that VSTs are a promising treatment option for managing these infections. ^{1 2 5 7 11}

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Long-Term Follow-Up after Adoptive Transfer of BK-Virus-Specific T Cells in Hematopoietic Stem Cell Transplant Recipients. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

The role of CD4(+) T cells in BKV-specific T cell immunity. [2021]

3. United States 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. [2022]

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

Role of Virus-Specific T Cell Therapy for Cytomegalovirus and BK Infections in Kidney Transplant Recipients. [2023]

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

Phenotypic and functional characterization of circulating polyomavirus BK VP1-specific CD8+ T cells in healthy adults. [2021]

6. United States 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. [2013]

7. Denmark pubmed.ncbi.nlm.nih.gov

Viral specific T cell therapy in kidney transplant recipients - A single-center experience. [2023]

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

Restoring antiviral immunity with adoptive transfer of ex-vivo generated T cells. [2023]

9. United States 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. [2022]

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

Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. [2022]

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

Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. [2023]