BK CTL for Viral Infections

Recruiting at 7 trial locations

Overseen By Lauren Harrison

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: New York Medical College

Must not be taking: Steroids, Thymoglobulin, Alemtuzumab, 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: 5

Duration: 12 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

BK cytotoxic T cells (CTLs) manufactured with the Miltenyi CliniMACS Prodigy Cytokine Capture System will be safe and effective in decreasing specific viral load in children, adolescents and young adults (CAYA) with refractory BK infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) or with primary immunodeficiencies (PID).

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 treatments like high-dose steroids or have had specific therapies recently. It's best to discuss your current medications with the trial team.

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

Research shows that BK virus-specific cytotoxic T cells (CTLs) can effectively target and destroy BK virus-infected cells, which is promising for treating BK virus complications in kidney transplant patients. Studies have demonstrated that these T cells can be generated and expanded in the lab, showing specificity and functionality in targeting the virus, suggesting potential for use in cellular immunotherapy. ^{1 2 3 4 5}

Is BK CTL treatment safe for humans?

The use of cytotoxic T lymphocytes (CTLs) for viral infections, including BK virus, has been studied in transplant patients, showing minimal toxicity, mainly localized swelling, and no severe side effects. This suggests that CTL treatments are generally safe for humans. ^{6 7 8 9 10}

How is the BK CTL treatment different from other treatments for viral infections?

BK CTL treatment is unique because it uses specially prepared immune cells called cytotoxic T lymphocytes (CTLs) that are trained to target and destroy cells infected with the BK virus and other viruses. This approach is different from standard antiviral drugs because it directly harnesses the body's immune system to fight the infection, potentially offering a more targeted and effective treatment for patients who have undergone stem cell transplants. ^{7 11 12 13 14}

Research Team

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Eligibility Criteria

This trial is for children, adolescents, and young adults aged 0.1 to 30.99 years with stubborn BK virus infections after a stem cell or organ transplant or those with primary immunodeficiencies. Participants must have tried antiviral treatments without success or cannot tolerate them due to side effects like kidney damage.

Inclusion Criteria

I have a BK virus infection that hasn't improved with treatment or I can't tolerate the treatment.

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

I can do most of my daily activities without help.

Exclusion Criteria

Patients unwilling or unable to comply with the protocol or unable to give informed consent

Any medical condition which could compromise participation in the study according to the investigator's assessment

You are currently participating in another research study for treating a certain type of infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Eligible patients with refractory BK infection will receive up to 5 infusions of BK CTLs that are donor derived

12 weeks

Up to 5 visits (in-person) for infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BK CTL

Trial Overview The study tests whether special immune cells called BK cytotoxic T cells (CTLs) can reduce the BK virus in patients who haven't responded well to other treatments post-transplantation or those with immune deficiencies.

Participant Groups

Group I: BK CTL Experimental Treatment 1 Intervention

Eligible patients with refractory BK infection will receive up to 5 infusions of BK CTLs that are donor derived.

BK CTL is already approved in United States, European Union for the following indications:

Approved in United States as BK CTL for:

• Refractory BK infections post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT)
• Refractory BK infections in patients with primary immunodeficiencies (PID)

Approved in European Union as BK CTL for:

• Refractory BK infections post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT)
• Refractory BK infections in patients with primary immunodeficiencies (PID)

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Medical College of Wisconsin

Collaborator

Trials

645

Recruited

1,180,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Findings from Research

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 involving 68 kidney transplant recipients (KTRs) found that BK virus (BKV)-specific T cell immunity, measured by the ELISPOT assay, is significantly higher in KTRs with cleared viremia compared to those with no viremia or ongoing BK viremia, suggesting a link between T cell response and viral clearance.

The results indicate that higher T cell responses in the controller group (those with less than 3 months of viremia) predict better outcomes, as they had significantly higher responses compared to the noncontroller group, highlighting the potential of the BKV-ELISPOT assay in predicting the risk of BK virus-associated nephropathy (BKVN).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Usefulness of BK virus-specific interferon-γ enzyme-linked immunospot assay for predicting the outcome of BK virus infection in kidney transplant recipients. Bae, H., Na, DH., Chang, JY., et al.[2021]

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]

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]

A specific CTL clone (BK-20) was found to selectively kill Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) but not normal B lymphoblasts, indicating its potential for targeted therapy against certain cancer cells.

The study revealed that the sensitivity of Burkitt lymphoma lines to CTL lysis is influenced by their cellular phenotype, as only one of the EBV-infected sublines became sensitive to CTLs, highlighting the importance of cellular characteristics in immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differentiation-dependent sensitivity of human B-cell-derived lines to major histocompatibility complex-restricted T-cell cytotoxicity. Torsteinsdottir, S., Masucci, MG., Ehlin-Henriksson, B., et al.[2019]

A new method allows for the rapid generation of polyclonal cytotoxic T lymphocytes (CTLs) that target 15 different viral antigens from 7 viruses, which are common causes of severe infections after hematopoietic stem cell transplantation, in just 10 days.

This approach enhances the effectiveness of CTLs by reducing competition between antigens and increasing the variety of virus-specific T cells, making it a promising and cost-effective alternative to traditional antiviral treatments for transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections. Gerdemann, U., Keirnan, JM., Katari, UL., et al.[2021]

Cytomegalovirus (CMV) reactivation poses significant risks for immunocompromised patients, such as those undergoing hematopoietic progenitor cell transplantation or living with HIV, leading to severe health complications despite antiviral treatments.

Recent advances in immunotherapy, including the adoptive transfer of CMV-specific T cell clones from seropositive donors, show promise in enhancing CMV-specific immunity and effectively treating CMV reactivation in these vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for cytomegalovirus (CMV) disease in immunocompromised patients. Lim, JB., Kwon, OH., Kim, HS., et al.[2005]

A new method for expanding donor-derived EBV-specific cytotoxic T cells (CTLs) has been developed, allowing for the generation of over 80 million CTLs in 5 weeks, which is promising for clinical use in patients undergoing partially mismatched related donor (PMRD) transplantation.

These CTLs are highly specific to donor cells and do not attack recipient cells, showing potential for safe application in preventing EBV-induced lymphoma post-transplantation, while also demonstrating properties that enhance their survival and ability to migrate into tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro generation of Epstein-Barr virus-specific cytotoxic T cells in patients receiving haplo-identical allogeneic stem cell transplantation. Musk, P., Szmania, S., Galloway, AT., et al.[2019]

In a study of 114 patients receiving EBV-specific cytotoxic T lymphocyte (CTL) infusions, the treatment showed minimal toxicity and effectively prevented EBV-related lymphoproliferative disease (LPD), with no cases in the 101 patients who received prophylaxis.

Among the 13 patients treated for existing LPD, 11 achieved sustained complete remissions, demonstrating the efficacy of CTLs in treating this condition, with functional CTLs persisting for up to 9 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Heslop, HE., Slobod, KS., Pule, MA., et al.[2023]

Natural killer-cytotoxic T lymphocytes (NK-CTL) can effectively recognize and kill cells infected with cytomegalovirus (CMV) through a unique mechanism involving the HLA-E molecule, which allows them to bypass the usual immune evasion strategies of the virus.

This ability of NK-CTL to target not only CMV-infected cells but also allogeneic cells expressing certain HLA-Cw alleles raises concerns for transplantation, as it may lead to unwanted immune responses against transplanted tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-E-restricted recognition of human cytomegalovirus by a subset of cytolytic T lymphocytes. Romagnani, C., Pietra, G., Falco, M., et al.[2023]

Virus-specific cytotoxic T lymphocytes (CTLs) play a crucial role in the immune response against viral infections by recognizing and eliminating virus-infected cells, which is essential for controlling infections like HIV and SIV.

Despite the strong activity of CTLs against HIV/SIV, the virus can persist and replicate due to the host's immune response failing to fully contain it, with certain HLA/MHC-I genotypes linked to the rate of AIDS progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of MHC-I genotypes with disease progression in HIV/SIV infections. Nomura, T., Matano, T.[2021]

Polyclonal Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) have shown promise in treating EBV-associated malignancies, indicating their potential effectiveness in targeting specific cancers.

The chapter discusses strategies to enhance the antitumor activity of these EBV-specific CTLs, which could lead to improved T cell therapies for various tumors with known antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell therapies. Gottschalk, S., Bollard, CM., Straathof, KC., et al.[2019]

A new method was developed to measure how different types of immune cells, particularly T cells, respond to killing by cytotoxic T lymphocytes (CTLs), revealing that T cells are generally more susceptible to CTL-mediated killing than B or NK cells.

The study found that memory T cells, especially those marked by CCR5+ or HLA-DR+, are highly susceptible to CTL killing, which helps explain the loss of certain CD4 T cell subsets during chronic HIV infection and identifies potential targets for addressing viral reservoirs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential susceptibility of leukocyte subsets to cytotoxic T cell killing: implications for HIV immunopathogenesis. Liu, J., Roederer, M.[2007]

References

1. United States 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. [2022]

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

BK virus-specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation. [2021]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Usefulness of BK virus-specific interferon-γ enzyme-linked immunospot assay for predicting the outcome of BK virus infection in kidney transplant recipients. [2021]

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

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

5. Germany pubmed.ncbi.nlm.nih.gov

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

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

Differentiation-dependent sensitivity of human B-cell-derived lines to major histocompatibility complex-restricted T-cell cytotoxicity. [2019]

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

Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections. [2021]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for cytomegalovirus (CMV) disease in immunocompromised patients. [2005]

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

In vitro generation of Epstein-Barr virus-specific cytotoxic T cells in patients receiving haplo-identical allogeneic stem cell transplantation. [2019]

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

Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. [2023]

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

HLA-E-restricted recognition of human cytomegalovirus by a subset of cytolytic T lymphocytes. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Association of MHC-I genotypes with disease progression in HIV/SIV infections. [2021]

13. Germany pubmed.ncbi.nlm.nih.gov

T cell therapies. [2019]

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

Differential susceptibility of leukocyte subsets to cytotoxic T cell killing: implications for HIV immunopathogenesis. [2007]