Cytotoxic T Lymphocytes for Virus-Related Cancer

Overseen By Amanda L. Olson, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Antivirals

Must not be taking: Prednisone, ATG, DLI, Campath

Disqualifiers: Uncontrolled infections, Active acute GVHD, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 56 days

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how effectively a special type of immune cell, called cytotoxic T lymphocytes, can combat viruses linked to certain cancers, particularly in patients who have undergone transplants. These cells, known as allogeneic BK-specific cytotoxic T-lymphocytes, are lab-created from donated blood cells and target BK and JC viruses, which can cause infections and worsen cancer. Individuals with a cancer diagnosis, HIV/AIDS, or an organ transplant who show signs of BK or JC virus might be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that patients must be able to reduce steroids to less than 0.5 mg/kg/day of prednisone. If you are on antiviral therapy like cidofovir or leflunomide without response, you can still participate.

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

Research has shown that special immune cells, called allogeneic BK-specific cytotoxic T lymphocytes, are generally safe for humans. In earlier studies, patients who received these cells for viral infections after certain transplants tolerated the treatment well, with no serious side effects reported. These findings suggest that the treatment might be safe for patients with cancers related to BK and JC viruses. However, as this is a Phase 2 trial, the researchers are still studying its safety further. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for virus-related cancers, which often rely on chemotherapy and radiation, the therapy being studied uses allogeneic BK-specific cytotoxic T-lymphocytes. These are specially engineered immune cells designed to target and destroy cancer cells linked to the BK virus. This targeted approach not only offers the potential for fewer side effects compared to traditional therapies but also enhances the body's natural immune response to fight cancer. Researchers are excited about this treatment because it represents a shift towards more personalized and precise cancer therapies, potentially improving outcomes for patients with virus-related cancers.

What evidence suggests that this treatment might be an effective treatment for virus-related cancer?

Research has shown that a special type of immune cell, called allogeneic BK-specific cytotoxic T cells, can help treat cancers linked to the BK virus. In this trial, participants will receive these T cells, made from donated blood, which have been safely used to manage problems caused by the BK virus after stem cell transplants. Early results suggest that these cells can find and destroy cancer cells infected by the virus, potentially treating these types of cancers. Specifically, patients with a severe brain infection called progressive multifocal leukoencephalopathy improved after receiving this treatment. Overall, these T cells offer a promising way to fight virus-related cancers. ^{5 6 7 8 9}

Who Is on the Research Team?

Amanda Olson

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with various malignancies, HIV/AIDS, history of organ transplant, or Merkel cell carcinoma linked to BK/JC viruses. Participants must have measurable disease and be willing to use contraception if applicable. Excluded are those on high-dose steroids, recent recipients of certain immune therapies, or with active severe infections.

Inclusion Criteria

I have cancer, HIV/AIDS, a history of organ transplant, or Merkel cell tumors with measurable disease.

I can reduce my steroid use to less than 0.5 mg/kg/day of prednisone.

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

Exclusion Criteria

I am currently experiencing moderate to severe symptoms of graft-versus-host disease.

I am not currently on high doses of prednisone, nor have I recently received ATG, DLI, or Campath treatments.

I don't have any uncontrolled infections or I've been stable on treatment for them.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive allogeneic BK-specific cytotoxic T-lymphocytes intravenously over 30 minutes. Eligible patients may receive up to 19 additional infusions at least 2 weeks apart.

Up to 56 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of acute GVHD and adverse events.

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic BK-specific Cytotoxic T-lymphocytes

Trial Overview The study tests donor-derived cytotoxic T lymphocytes (CTLs) against BK and JC viruses in patients with related malignancies. CTLs are blood cells grown in a lab designed to fight these specific viral infections that can complicate transplants.

How Is the Trial Designed?

Group I: Treatment (BK-specific cytotoxic T lymphocytes) Experimental Treatment 2 Interventions

Patients receive allogeneic BK-specific cytotoxic T-lymphocytes IV over 30 minutes. Patients achieving partial response, stable disease, or progressive disease are eligible for 19 additional infusions of CTL occurring at least 2 weeks after the previous CTL infusion if they meet the eligibility criteria for subsequent therapy.

Allogeneic BK-specific Cytotoxic T-lymphocytes is already approved in United States, European Union for the following indications:

Approved in United States as Allogeneic BK-specific Cytotoxic T-lymphocytes for:

• BK virus infection
• JC virus infection
• Hemorrhagic cystitis
• BK nephropathy

Approved in European Union as Allogeneic BK-specific Cytotoxic T-lymphocytes for:

• BK virus infection
• JC virus infection
• Progressive multifocal leukoencephalopathy (PML)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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]

Cytotoxic T cells specific to adult T cell leukemia virus (ATLV) were successfully induced in vitro from peripheral blood leukocytes of healthy donors, demonstrating the potential for targeted immune responses against ATLV-bearing cells.

The induced T cells showed selective cytotoxicity against ATLV-positive cells while sparing healthy cells, indicating a mechanism of HLA-restricted recognition and suggesting the presence of multiple distinct target antigens for effective immunotherapy against ATLV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment of human cytotoxic T cell lines specific for human adult T cell leukemia virus-bearing cells. Kannagi, M., Sugamura, K., Sato, H., et al.[2006]

Human cytotoxic T lymphocyte lines can be effectively generated by stimulating peripheral blood lymphocytes with allogeneic Epstein-Barr virus-transformed lymphoblastoid cell lines, demonstrating the potential for targeted immune responses.

The study found that stimulation with Daudi cells specifically led to the creation of T cell lines that recognize the DR6 antigen, highlighting a mechanism for generating allospecific T cells that could be useful in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term human cytolytic T-cell lines allospecific for HLA-DR6 antigen are OKT4+. Krensky, AM., Reiss, CS., Mier, JW., et al.[2019]

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]

Immunizing C57BL/6J mice with BK virus (BKV)-transformed cells revealed a common cell surface antigen that is likely linked to the viral transplantation antigen, present in both syngeneic and allogeneic cell lines.

Cytotoxicity tests showed that effective immune response (cytolysis) only occurred when the target cells expressed the same H2 haplotype as the effector lymphocytes, indicating a specific requirement for matching immune markers in the response to BKV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell-mediated immune reaction against BK virus-transformed cells. Mäntyjärvi, R., Karjalainen, H., Laaksonen, M.[2019]

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]

A new method to monitor BKV-specific T-cell immunity was developed, allowing for the detection of CD4+ and CD8+ T-cell responses in kidney transplant patients with high levels of BKV-DNA, which is crucial for understanding the immune response to polyoma BK virus.

This method can help assess how reducing immunosuppression affects BKV immunity and the role of specific T cells in the development of polyoma BK virus-associated nephropathy (PVAN), highlighting its potential for improving patient management in transplant settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA type-independent method to monitor polyoma BK virus-specific CD4 and CD8 T-cell immunity. Hammer, MH., Brestrich, G., Andree, H., et al.[2023]

In a study of healthy BKV-seropositive individuals, most had CD4(+) and CD8(+) T cells that specifically responded to BK polyomavirus antigens, indicating a robust immune response against the virus.

The CD4(+) T cells not only produced key cytokines like IFN-gamma and TNF-alpha but also showed signs of cytotoxic activity, suggesting they could help control BKV reactivation and prevent complications in at-risk populations, such as kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults. Zhou, W., Sharma, M., Martinez, J., et al.[2008]

Cytotoxic T cells (Tc) play a crucial role in rejecting incompatible tissue grafts and can significantly reduce virus levels in infected organs when transferred to compatible hosts, as shown in studies with ectromelia and influenza virus infections in mice.

Despite evidence of tumor-specific antigens on cancer cells, there is limited evidence for the presence of specific Tc that could target and control tumor growth, suggesting potential challenges in generating effective immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are cytotoxic T cells a common homeostatic mechanism in responses to viruses, homografts and tumours? Ada, GL., Yap, KL.[2005]

A specific cytotoxic T-lymphocyte clone was able to significantly reduce the growth of fibrosarcomas in mice, demonstrating its potential as a targeted cancer therapy.

Combining the tumor-specific transplantation antigen with cyclophosphamide and the cytotoxic T-lymphocyte clone led to a dramatic reduction in tumor size and increased survival time in treated mice, highlighting the efficacy of this multi-faceted approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy with a tumor-infiltrating lymphocyte clone, soluble antigen, and cyclophosphamide. Komichi, H., Smith, S., Kahan, BD.[2019]

The phase 2 study involved 50 recipients of allogeneic hematopoietic stem cell transplants who received donor-derived cytomegalovirus (CMV)-specific cytotoxic T cells, aiming to evaluate the efficacy of this treatment.

Outcomes were compared with a control group of patients who underwent the same transplant procedure but did not receive the CMV-specific CTLs, providing insights into the potential benefits of this immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy versus T lymphocytes for CMV. Heslop, HE.[2021]

Citations

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Study Details | NCT02479698 | Cytotoxic T Lymphocytes in ... This phase II trial studies how well donor cytotoxic T lymphocytes work in treating patients with malignancies with BK and/or JC virus. Cytotoxic T ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33929874/

Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy ... Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1801540

Allogeneic BK Virus–Specific T Cells for Progressive ... We report the results of using third-party–produced, cryopreserved, most closely HLA-matched, BK virus–specific T cells to treat three patients with PML.

4. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/allogeneic-bk-specific-cytotoxic-t-lymphocytes

Definition of allogeneic BK-specific cytotoxic T lymphocytes Allogeneic cytotoxic T lymphocytes (CTLs) that are specifically reactive to BK virus (BKV), with potential antiviral activity.

5. trial.medpath.com trial.medpath.com/clinical-trial/80b2f38e9c18c5b4/ii-assessing-effect-bk-specific-ctl-lines-ex-vivo-expansion

Cytotoxic T Lymphocytes in Treating Patients With ... - MedPath This phase II trial studies how well donor cytotoxic T lymphocytes work in treating patients with malignancies with BK and/or JC virus. Cytotoxic T ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10166368/

Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy ... To prospectively test the efficacy and safety of most closely HLA-matched third party BK virus (BKV)-specific cytotoxic T lymphocytes (CTLs) to ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118718089

Safety and Efficacy of Virus-Specific Cytotoxic T- ... Safety and efficacy of virus-specific cytotoxic T-lymphocytes manufactured by the IFN-g cytokine capture system for the treatment of refractory adenovirus.

8. astctjournal.org astctjournal.org/article/S1083-8791(19)31082-1/fulltext

The Safety and Efficacy of Targeted Virus Specific ... Preliminary results of this pilot study demonstrate that VST are safe and efficacious in CAYA with refractory viral infections after alloHSCT, SOT or with PID.

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

Virus-Specific T Cells for the Treatment of Systemic Infections ... This article provides a practical guide to VST therapy by reviewing manufacturing techniques, donor selection, and treatment indications.