CTL Therapy for BK Virus Infection

(BK-CTLs Trial)

Overseen By Megan Atkinson

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Steroids, Thymoglobulin, Campath, others

Disqualifiers: Acute GVHD, HIV, Pregnancy, 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: Unknown

Duration: 8 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if specially prepared immune cells, called cytotoxic T lymphocytes (CTLs), can reduce the BK virus in individuals with related symptoms following treatments like stem cell transplants, kidney transplants, or chemotherapy. The trial focuses on those showing signs of bladder inflammation, such as blood in urine or pain during urination, who have tested positive for the BK virus. Individuals with these symptoms who have undergone the mentioned procedures may be suitable candidates for the trial. As an Early Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain steroids or immunosuppressive drugs close to the time of the infusion.

Is there any evidence suggesting that BK-virus specific CTLs are likely to be safe for humans?

Research has shown that BK-virus specific immune cells, known as cytotoxic T lymphocytes (CTLs), are generally safe for humans. Studies have found that these virus-targeting cells do not cause harmful reactions when introduced into the body. Patients experienced no negative effects during the infusion process. Additionally, no new cases of graft-versus-host disease, where donor cells attack the patient's body, or rejection of transplanted organs or tissues occurred. This suggests the treatment does not harm transplanted organs or tissues.

While these findings are encouraging, they come from early research stages. The treatment remains under close monitoring to ensure safety and effectiveness. Overall, the initial data supports the safety of BK-virus specific CTLs in managing infections related to the BK virus. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for BK virus infection, like antiviral drugs and supportive care, focus on managing symptoms and trying to control the virus indirectly. But BK-virus specific cytotoxic T lymphocytes (CTLs) work differently, targeting the virus directly with immune cells that are specifically trained to recognize and destroy BK-virus-infected cells. Researchers are excited about this approach because it harnesses the body’s own immune system for a more precise attack, potentially leading to better outcomes with fewer side effects. This targeted immune response could offer a more powerful and efficient treatment option compared to traditional methods.

What evidence suggests that BK-virus specific CTLs might be an effective treatment for BK virus infection?

Research has shown that special immune cells, called T cells, might help treat BK virus infections. In this trial, participants will receive BK-virus specific CTLs, designed to target and reduce BK virus levels. Studies have found that these T cells can lower BK virus levels in patients who have undergone a stem cell or organ transplant. Specifically, one study found that 82% of patients treated with these T cells had the virus completely eliminated. These specific T cells could help manage BK virus infections and related issues, such as kidney problems, after transplants. Although more research is needed, the early results are promising. ^{1 3 4 6 7}

Who Is on the Research Team?

Caitlin Elgarten, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for immunocompromised transplant patients aged 0.1 to 25 years with BK virus infections post-transplant or chemotherapy, experiencing symptoms like blood in urine and pain during urination. Participants need a related donor with T-cell response to the virus, must not be on certain steroids or other experimental treatments for BK virus, and should have a performance status over 30%. Pregnant women and those unwilling to use birth control are excluded.

Inclusion Criteria

I am between 1 month and 25 years old.

I need a new donor because my original one can't help. The new donor matches me closely.

I am a woman who can have children and my pregnancy test is negative.

Exclusion Criteria

Known human anti-mouse antibodies

I am taking steroids equivalent to more than 0.5 mg/kg of prednisone at the time of or within 3 days before my planned infusion.

I am not pregnant, breastfeeding, and willing to use birth control during the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BK virus-specific CTLs to decrease viral load

8 weeks

Regular visits for CTL infusions and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Monitoring visits for viral load assessment

What Are the Treatments Tested in This Trial?

Interventions

• BK-virus specific CTLs

Trial Overview The study tests whether special immune cells called BK-virus specific CTLs can reduce viral load in patients with BK Virus after stem cell or kidney transplants, or chemotherapy. These CTLs are made using a system called Miltenyi CliniMACS Prodigy Gamma-capture.

How Is the Trial Designed?

Group I: BK cystitis and/or nephropathy Experimental Treatment 1 Intervention

All patients with symptoms that are consistent with BK cystitis and/or nephropathy (frequency, dysuria, hematuria, elevated creatinine) will have serum quantitative DNA PCR for BK virus level measured in log copies per mL (results also expressed in copies per milliliter), performed in the Children's Hospital of Philadelphia Infectious Disease Diagnostics Laboratory

BK-virus specific CTLs is already approved in United States, European Union for the following indications:

Approved in United States as BK-virus specific CTLs for:

• BK virus infection in immunocompromised transplant patients
• BK virus-associated hemorrhagic cystitis

Approved in European Union as BK-virus specific CTLs for:

• BK virus infection in immunocompromised transplant patients
• BK virus-associated nephropathy

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Published Research Related to This Trial

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]

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]

A new cellular immunotherapy approach was developed to reactivate BKV-specific cytotoxic T cells from kidney transplant recipients, which could help prevent BKV-associated interstitial nephritis, a serious complication after transplantation.

The reactivated T cells showed strong specificity for BKV-infected cells while sparing healthy cells, indicating a targeted and potentially safer treatment option for managing BKV infections in immunocompromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dendritic cells pulsed with polyomavirus BK antigen induce ex vivo polyoma BK virus-specific cytotoxic T-cell lines in seropositive healthy individuals and renal transplant recipients. Comoli, P., Basso, S., Azzi, A., et al.[2022]

In a study of 77 adult patients after hematopoietic cell transplantation, those with BK virus reactivation had lower CD4 T-cell counts, indicating a potential link between T-cell immunity and BK virus disease.

The presence of BK virus-specific CD4 T cells producing Th1 cytokines was associated with lower rates of urinary symptoms, suggesting that these T cells play a crucial role in controlling BK virus reactivation and its clinical manifestations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BK virus-specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation. Espada, E., Cheng, MP., Kim, HT., et al.[2021]

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 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]

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]

A study involving 41 patients (38 HSCT and 3 SOT recipients) showed that T cell therapy targeting BK polyomavirus (BKPyV) resulted in an impressive overall response rate of 86% for BK viremia and 100% for hemorrhagic cystitis, indicating its efficacy in managing BKPyV-related complications.

The treatment was found to be safe, with no significant side effects such as infusional toxicity or graft-versus-host disease, suggesting that virus-specific T cell therapy could be a promising option for immunocompromised patients at risk for BKPyV complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients. Nelson, AS., Heyenbruch, D., Rubinstein, JD., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7686882/

Virus-specific T-cell therapy to treat BK polyomavirus infection ... Key Points. Virus-specific T cells can be effectively used to treat BKPyV infections in HSCT and solid organ transplant recipients.

2. ashpublications.org ashpublications.org/bloodadvances/article-abstract/4/22/5745/474204

Virus-specific T-cell therapy to treat BK polyomavirus infection ... Key Points. Virus-specific T cells can be effectively used to treat BKPyV infections in HSCT and solid organ transplant recipients.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10758681/

BK viral infection: A review of management and treatment - PMC BK viral infection is a significant post-transplant infection, which can result in kidney dysfunction if left unaddressed.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0924857924002498

Advances in virus-specific T-cell therapy for polyomavirus ... The overall response results were 82 complete response, 33 partial response, 35 no response, and 10 no-outcome-reported. This review underscores the importance ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636724008091

Incidence, Risk Factors, and Outcomes of BK Hemorrhagic ... BK hemorrhagic cystitis (BK-HC) is a common complication following hematopoietic stem cell transplantation (HSCT), particularly when posttransplant ...

6. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/jmv.70357

A Phase I Study Evaluating Safety and Tolerability of Viral ... In summary, BK-specific T-cell therapy shows potential for being a safe strategy for managing BKPyV infections post-kidney transplantation to ...

7. academic.oup.com academic.oup.com/jpids/article/13/Supplement_1/S49/7615748

Virus-Specific T Cells for the Treatment of Systemic Infections ... Viral infections are a major source of morbidity and mortality in the context of immune deficiency and immunosuppression following allogeneic ...