T Cell Therapy for Cytomegalovirus

Overseen By Mari H Dallas, MD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: Mari Dallas

Must not be taking: Antithymocyte globulin, Virus-specific T cells

Disqualifiers: Pregnancy, Other viral infections, GVHD, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with cytomegalovirus (CMV) infections following a stem cell transplant. The treatment uses special T-cells from a donor's blood, designed to help the immune system combat CMV. It involves a one-time infusion of these CMV-specific adoptive T-cells, followed by a four-week monitoring period. Patients who have undergone a stem cell transplant, are over 30 days post-transplant, and continue to struggle with CMV despite standard antiviral treatments might be suitable candidates for this study. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients with certain conditions requiring high doses of steroids or recent treatment with specific therapies are excluded, which might imply some restrictions. It's best to discuss your current medications with the trial team.

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

Previous studies have shown that adoptive T-cell therapy with CMV-specific T-cells is safe for patients. Research indicates that these specially selected donor T-cells can help combat cytomegalovirus (CMV) infections. Several studies found that these treatments were well-tolerated, with most participants experiencing no serious side effects. The evidence suggests that these T-cells can effectively control CMV without causing major issues for patients. However, since adoptive T-cell therapy remains experimental and lacks FDA approval, some safety aspects may still be unknown. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CMV-specific adoptive T-cell therapy because it offers a targeted approach against cytomegalovirus (CMV) infections that is different from the typical antiviral medications currently used. Unlike standard treatments such as ganciclovir or valganciclovir, which can affect both healthy and infected cells, this therapy uses specially engineered T-cells that precisely target and combat CMV-infected cells. This specificity not only enhances the treatment's effectiveness but also reduces potential side effects associated with broader antiviral drugs. Additionally, the possibility of a one-time infusion that can provide lasting protection is a significant advantage over daily medication regimens.

What evidence suggests that CMV specific adoptive T-cells might be an effective treatment for cytomegalovirus?

Research has shown that CMV-specific adoptive T-cell therapy, which participants in this trial will receive, could help fight cytomegalovirus (CMV) infections. Studies have found that these specially chosen T-cells help control CMV, especially after transplants. For instance, patients who received this therapy experienced fewer instances of the virus returning. This treatment effectively manages tough CMV infections and prevents them. Overall, evidence suggests that this therapy could be a useful option for dealing with CMV infections. ^{1 2 3 4 6}

Who Is on the Research Team?

Mari H Dallas, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients who've had a bone marrow transplant and are over 30 days post-transplant, with CMV infections not improving after antiviral therapy or those experiencing side effects from such treatments. Participants need to be able to consent and use contraception if applicable. Excluded are pregnant/breastfeeding women, recent recipients of certain immune therapies, those with other viral infections or active severe graft vs. host disease.

Inclusion Criteria

My viral load hasn't improved after 2 weeks of antiviral treatment, or I've had new or ongoing symptoms, or I can't tolerate the medication, or my CMV infection has come back twice.

I am capable of limited self-care and spend more than half of my waking hours out of bed.

I agree to use birth control during the study.

Exclusion Criteria

I am currently experiencing severe graft vs. host disease or need high doses of steroids.

I have a viral infection that is not CMV.

I have not received virus-specific T cell therapy in the last 6 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time infusion of CMV-specific adoptive T-cells

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Regular monitoring visits

Extended Follow-up

Participants are monitored for adverse events and response rate up to 100 days after transplant

Up to 100 days

What Are the Treatments Tested in This Trial?

Interventions

• CMV specific adoptive t-cells

Trial Overview The study tests the feasibility of using donor-derived T-cells that target cytomegalovirus (CMV) in patients who have received a bone marrow transplant. This cell-based immunotherapy aims to bolster the patient's immune response against CMV infection.

How Is the Trial Designed?

Group I: CMV specific adoptive t-cells Experimental Treatment 1 Intervention

This study involves a one-time infusion of the experimental CMV specific adoptive t-cells. After this infusion, patients will be followed for 4 weeks.

CMV specific adoptive t-cells is already approved in United States, European Union, China for the following indications:

Approved in United States as CMV-specific T-cells for:

• Investigational for CMV infections post-transplant

Approved in European Union as CMV-specific T-cells for:

• Investigational for CMV infections post-transplant

Approved in China as CMV-specific T-cells for:

• Investigational for CMV infections post-transplant

Who Is Running the Clinical Trial?

Mari Dallas

Lead Sponsor

Trials

2

Recruited

40+

Published Research Related to This Trial

In a study involving 16 patients, treatment with polyclonal CMV-specific T-cell lines led to significant in-vivo expansion of these immune cells, effectively reconstituting viral immunity against CMV infection after transplantation.

The use of these T-cell lines was shown to be effective, as eight patients did not require antiviral drugs, and only two experienced subsequent reactivation of the virus, highlighting the potential of this therapy in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Peggs, KS., Verfuerth, S., Pizzey, A., et al.[2023]

In a study of 104 patients receiving CMV-specific cytotoxic T lymphocytes (CMV-CTLs) for CMV viremia after allogeneic transplant, the source of CMV-CTLs (either from primary or third-party donors) did not affect the likelihood of achieving important immune recovery milestones.

Patients with higher baseline CD4+ T cell counts (>50 × 10^6/L) showed better responses to CMV-CTL therapy, leading to improved overall survival and reduced risk of CMV-related death, highlighting the importance of baseline immunity in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Fabrizio, VA., Rodriguez-Sanchez, MI., Mauguen, A., et al.[2021]

A 21-year-old male patient developed possible CMV pneumonia three months after receiving CAR-T cell therapy for relapsed B-ALL, highlighting the risk of late-phase viral reactivation in immunocompromised patients.

Despite initial improvement with antiviral treatment, the patient's condition worsened after stopping one of the medications, leading to respiratory failure and death, emphasizing the need for careful monitoring and management of viral infections post-CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Fatal cytomegalovirus pneumonia after CAR-T cell therapy in the long-term follow-up. Cheng, J., Huang, J., Cao, W., et al.[2023]

CAR T-cell therapy is an effective treatment for blood cancers but can lead to serious side effects like cytokine release syndrome and prolonged immunosuppression, increasing the risk of infections.

In a case study of a 64-year-old man with multiple myeloma, a history of cytomegalovirus (CMV) infection worsened after CAR T-cell therapy, highlighting the need for better strategies to prevent and manage CMV infections in patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytomegalovirus infection in chimeric antigen receptor T-cell recipients. Abreu, M., Varghese, J., Santiago, M., et al.[2023]

A new clinical-scale protocol was developed to generate CMV-specific T cells from a single 500-mL blood draw, allowing for a more efficient and less time-consuming method compared to traditional techniques that require live virus and leukapheresis.

The generated CMV-specific T cells effectively lysed CMV-infected cells and showed reduced alloreactivity, indicating that this method not only produces a high quantity of functional T cells but also minimizes the risk of unwanted immune responses in transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Rauser, G., Einsele, H., Sinzger, C., et al.[2022]

CAR-T cell therapy has shown remarkable effectiveness in treating difficult cases of cancers like acute lymphoblastic leukemia and lymphomas, but it can also lead to serious side effects such as cytokine release syndrome and neurological toxicities.

These adverse events, while potentially life-threatening, can be managed effectively with early recognition and treatment by trained medical teams, highlighting the importance of proper preparation and training in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. I: Structuring centers for the multidisciplinary clinical administration and management of CAR-T cell therapy patients. Clé, DV., Hirayama, AV., Alencar, AJ., et al.[2021]

CMV infection is a major risk after allogeneic stem cell transplantation, but reconstituting CMV-specific T cell responses can help protect patients from developing CMV disease.

Two strategies to enhance T cell immunity against CMV include transferring selected CMV-specific T cells directly from the donor to the patient and expanding these T cells in vitro using antigen presenting cells, both of which aim to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMV-specific T cell therapy. Einsele, H., Kapp, M., Grigoleit, GU.[2007]

CAR-T therapy has shown significant promise in treating patients with relapsed or refractory hematological cancers, but it can lead to severe immunological toxicities that require careful management.

Common toxicities associated with CAR-T therapy include cytokine-release syndrome and neurotoxicity, which can result in serious complications, highlighting the need for a multidisciplinary approach to patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities following CAR-T therapy for hematological malignancies. Hernani, R., Benzaquén, A., Solano, C.[2022]

The study successfully isolated CMV-specific cytotoxic T lymphocytes (CTLs) from donor leukocytes using a novel MHC class I peptide streptamer method, achieving a median purity of 90.2% and yielding 7.77 million functional CTLs.

This approach provides a promising non-toxic alternative for restoring CMV immunity in patients after hematopoietic stem cell transplantation, with the isolated CTLs demonstrating excellent viability and cytotoxicity for at least 72 hours post-collection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical-scale isolation of 'minimally manipulated' cytomegalovirus-specific donor lymphocytes for the treatment of refractory cytomegalovirus disease. Odendahl, M., Grigoleit, GU., Bönig, H., et al.[2014]

A novel method using synthetic CpG oligodeoxynucleotides and modified vaccinia Ankara (MVA) to expand CMV-specific CD4(+) and CD8(+) T cells resulted in a 30-fold increase in T cell populations within 10 days, demonstrating high efficacy for potential therapeutic use.

The expanded T cells showed minimal alloreactivity and strong cytotoxic activity against CMV, making this approach promising for managing CMV viremia in patients undergoing hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro expansion of polyclonal T-cell subsets for adoptive immunotherapy by recombinant modified vaccinia Ankara. La Rosa, C., Wang, Z., Lacey, SF., et al.[2008]

CAR-T therapy is highly effective in treating certain cancers, but it is associated with significant complications, particularly cytokine release syndrome and neurotoxicity.

In addition to the well-known side effects, there are various other CAR-T-specific adverse events that require careful management based on clinical experiences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of adverse events of CAR-T therapy]. Arai, Y.[2023]

An innovative in vitro system was developed to generate human cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) using autologous donor leucocytes coated with CMV antigens, effectively producing CTLs from seropositive donors.

The study demonstrated that CMV-specific CTLs could be inhibited by monoclonal antibodies targeting CMV-related proteins, indicating a potential mechanism for regulating CTL activity in therapeutic settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definition of human cytomegalovirus-specific target antigens recognized by cytotoxic T cells generated in vitro by using an autologous lymphocyte system. Charpentier, B., Michelson, S., Martin, B.[2006]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38184303/

Adoptive transfer of CMV-specific TCR-T cells for the ... Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3306600/

Adoptive Immunotherapy with CMV Specific Cytotoxic T ... Adoptive immunotherapy with cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) is an effective strategy for preventing and treating viral ...

3. ashpublications.org ashpublications.org/bloodadvances/article/5/2/496/474967/Adoptive-therapy-with-CMV-specific-cytotoxic-T

Adoptive therapy with CMV-specific cytotoxic T lymphocytes ... Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant.

4. academic.oup.com academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf232/8125789

Virus-Specific T-Cell Therapy for Prophylaxis and Treatment of ... Cytomegalovirus-specific T cells have been used in studies of primarily adult hematopoietic stem cell transplant recipients.

5. nature.com nature.com/articles/s41409-021-01499-0

specific cytotoxic T lymphocyte therapy resolve CMV ... The use of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) has shown advantages in controlling refractory and late CMV infection when combined with ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324908701828

Detailed analysis of cytomegalovirus (CMV)-specific T cells ... The adoptive transfer of CMV-specific T cells is a promising approach for controlling or preventing CMV reactivation because it has been demonstrated that ...