CAR T-Cells + CMV-MVA Triplex Vaccine for Non-Hodgkin's Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Active autoimmune, CNS disease, others

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

Compensation: Varies

Number of Visits: 5

Duration: 8 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for treating certain types of non-Hodgkin's lymphoma (NHL) that have not responded to treatment or have returned. It combines a modified immune cell therapy, called CAR T-cells (Anti-CD19-CAR CMV-specific T-lymphocytes), with the CMV-MVA Triplex Vaccine to assess their effectiveness against cancer cells. The goal is to determine if this combination is safe and can prevent cancer recurrence. This trial may suit those with intermediate or high-grade B-cell NHL who have not found success with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does exclude those using systemic steroids or chronic immunosuppressants. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that anti-CD19 CAR T-cell treatment may benefit people with B-cell lymphoma that has returned or is difficult to treat. In earlier studies, most participants tolerated these treatments well, though some experienced side effects like fever, tiredness, and low blood cell counts.

Regarding the vaccine, studies suggest that the CMV-MVA triplex vaccine is safe and can enhance the immune system to fight infections. Reported side effects are usually mild and may include soreness at the injection site and mild flu-like symptoms.

These treatments remain under investigation, and this early research stage focuses on ensuring their safety for people. Participants should discuss any concerns with the medical team conducting the study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for Non-Hodgkin's Lymphoma, which often involve chemotherapy and monoclonal antibodies, the CAR T-Cells + CMV-MVA Triplex Vaccine approach is unique because it combines genetically engineered T-cells with a specialized vaccine. This treatment uses anti-CD19-CAR CMV-specific T-lymphocytes to target and destroy cancer cells more precisely. Researchers are excited about this because the combination of CAR T-cells with the CMV-MVA triplex vaccine could enhance the immune response and potentially offer a more durable remission. This innovative method aims to improve effectiveness while minimizing side effects often associated with conventional therapies.

What evidence suggests that this trial's treatments could be effective for non-Hodgkin's lymphoma?

Research shows that a new treatment using specially engineered T-cells, called anti-CD19 CAR T-cells, may help treat B-cell non-Hodgkin's lymphoma, especially when it recurs or resists other treatments. These T-cells are designed to find and destroy cancer cells. In this trial, participants will receive these T-cells along with the CMV-MVA triplex vaccine. Studies suggest that this combination might enhance the treatment's effectiveness. The vaccine could strengthen the body's immune system, helping to prevent the cancer from returning. Early results indicate that this combined treatment approach could improve cancer control and increase treatment effectiveness. ^{1 2 3 6 7}

Who Is on the Research Team?

Leslie Popplewell, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults with relapsed or refractory B-cell non-Hodgkin lymphoma, who are CMV seropositive and have a life expectancy of at least 16 weeks. They must be in good physical condition (KPS >= 70), not pregnant, willing to use birth control, and without significant heart, liver or kidney issues. Excluded are those with active autoimmune disease on treatment, recent allogeneic stem cell transplant recipients, or anyone on investigational agents.

Inclusion Criteria

Alanine aminotransferase (ALT) < 2.5 x ULN

My cancer is confirmed to be a certain type of aggressive CD19+ cancer.

I have no allergies or adverse reactions to specific medical treatments or vaccines.

Exclusion Criteria

I am currently using steroids or immunosuppressant medications regularly.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents or cetuximab

I don't have any health issues that would prevent me from receiving chemotherapy or CAR T-cell therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis

Patients undergo leukapheresis to collect T cells for modification

1 day

1 visit (in-person)

Lymphodepletion

Patients receive lymphodepleting chemotherapy as per standard of care

1 week

Daily visits (in-person)

Treatment

Patients receive CMV-specific CD19-CAR T cells intravenously and CMV-MVA triplex vaccine intramuscularly

8 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Regular visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Anti-CD19-CAR CMV-specific T-lymphocytes
• Multi-peptide CMV-Modified Vaccinia Ankara Vaccine

Trial Overview The trial is testing genetically modified T-cells targeting CD19 on cancer cells plus a CMV-based vaccine after chemotherapy that reduces immune cells (lymphodepletion). It aims to see if this combination can help the body's immune system fight the lymphoma more effectively.

How Is the Trial Designed?

Group I: Treatment (CMV-specific CD19-CAR T cells, triplex vaccine) Experimental Treatment 10 Interventions

Patients undergo leukapheresis on day -30 and receive lymphodepleting chemotherapy on days -10 to -3 per SOC on study. Patients then receive CMV-specific CD19-CAR T cells IV on day 0 and CMV-MVA triplex vaccine IM on days 28 and 56 in the absence of unacceptable toxicity on study. Patients also undergo x-ray during screening and on study, as well as PET, CT, MRI, blood sample collection, and bone marrow biopsy on study and during follow-up.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A new clinical platform successfully generates CMV-CD19CAR T cells from healthy donors, achieving a high enrichment of CMV-specific T cells and a transduction efficiency of 27%, which is crucial for effective cancer treatment.

These CMV-CD19CAR T cells showed strong anti-tumor activity and maintained memory characteristics, indicating their potential for improved persistence and efficacy in treating B cell malignancies, with plans for a clinical trial in patients with non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large-scale manufacturing and characterization of CMV-CD19CAR T cells. Wang, X., Urak, R., Walter, M., et al.[2022]

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]

Bispecific CAR-T cells targeting both CD19 and CD20 have shown the ability to eliminate lymphoma cells that are negative for either antigen, providing a promising strategy to overcome treatment failures associated with CD19 CAR-T therapy.

Among the tested CAR structures, the loop2019 CAR demonstrated superior efficacy in eradicating lymphoma cell lines and primary cells from patients at very low doses, significantly prolonging survival in a mouse model, indicating its potential for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loop CD20/CD19 CAR-T cells eradicate B-cell malignancies efficiently. Chen, Z., Liu, Y., Chen, N., et al.[2023]

Vaccinating healthy donors with the Triplex vaccine before hematopoietic cell transplant (HCT) significantly increased levels of CMV-specific T cells in recipients, indicating enhanced immune protection against cytomegalovirus (CMV).

The Triplex vaccine was well-tolerated with minimal adverse events, and the approach shows promise for reducing the need for antiviral prophylaxis, which can hinder the development of CMV-specific immunity post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis. La Rosa, C., Aldoss, I., Park, Y., et al.[2023]

The CMVPepVax vaccine demonstrated safety in a phase 1b trial with 36 CMV-seropositive patients undergoing stem-cell transplantation, showing no adverse effects on transplant outcomes or unexpected serious adverse events.

Patients receiving the CMVPepVax vaccine had significantly better relapse-free survival compared to those under observation, suggesting potential clinical benefits that warrant further investigation in a phase 2 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Nakamura, R., La Rosa, C., Longmate, J., et al.[2022]

In a phase 2 trial involving 102 high-risk CMV-seropositive hematopoietic stem cell transplant recipients, the Triplex vaccine showed a trend towards reducing CMV reactivation, with 9.8% of Triplex recipients experiencing reactivation compared to 19.6% in the placebo group.

The Triplex vaccine was found to be safe, with no serious adverse events or deaths related to the vaccine, and it successfully increased levels of CMV-specific T cells, suggesting it effectively enhances the immune response against CMV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. Aldoss, I., La Rosa, C., Baden, LR., et al.[2023]

The study developed a whole-cell vaccine using K562 cells engineered to express CMV-pp65, CD40L, and OX40L, which effectively boosts CMV-specific cytotoxic T cells (CTLs) and enhances their antitumor responses in xenograft models.

Incorporating the inducible safety switch caspase9 (iC9) into the vaccine allows for controlled growth arrest of the engineered cells, addressing potential safety concerns associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

K562-Derived Whole-Cell Vaccine Enhances Antitumor Responses of CAR-Redirected Virus-Specific Cytotoxic T Lymphocytes In Vivo. Caruana, I., Weber, G., Ballard, BC., et al.[2021]

Anti-CD19 CAR T-cell therapy has shown remarkable efficacy in treating relapsed or refractory aggressive B-cell lymphomas, leading to durable remissions in patients who previously had no effective treatment options.

Three CAR T-cell therapies (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) are approved for use, each differing in their design, manufacturing processes, and safety profiles, highlighting the need for personalized approaches in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Abramson, JS.[2021]

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]

The study presents a novel strategy to enhance the effectiveness of CAR T cell therapy for leukemia and lymphomas by using CMV vaccination to boost the persistence and engraftment of CAR-redirected T cells after infusion.

This approach aims to address common challenges in CAR T cell therapy, such as short-lived T cell responses and the inability to reactivate T cells after disease relapse, potentially leading to more durable remissions in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of CMV-CD19 bi-specific CAR T cells with post-infusion in vivo boost using an anti-CMV vaccine. Wang, X., Diamond, DJ., Forman, SJ., et al.[2022]

In a study of 50 patients receiving CD19 CAR-T cell therapy, 36% experienced infectious complications, with a median time to infection of 225 days, indicating that infections can occur well after treatment.

Severe infections were common, with 54.8% leading to significant health issues, including hospitalization and even death in 6% of patients, highlighting the need for ongoing monitoring and improved antimicrobial prophylaxis strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience. Walker, B., Zimmer, AJ., Stohs, EJ., et al.[2023]

In a phase 2 clinical trial involving 20 patients with lymphoma or myeloma, the Triplex vaccine significantly enhanced the reconstitution of adaptive natural killer (NK) cells and CMV-specific T cells after autologous hematopoietic cell transplantation (auto-HCT), particularly in CMV-seronegative patients.

The vaccine led to a notable increase in adaptive NK cells and CMV-specific T cells, suggesting a potential for improved immune response post-transplant, although further research is needed to assess the clinical benefits of these immune enhancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation. Rashidi, A., La Rosa, C., Curtsinger, J., et al.[2023]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

Citations

1. nature.com nature.com/articles/s41409-025-02691-2

Safety and efficacy of autologous humanized CD19 CAR-T ... Limited research has evaluated humanized CD19-targeted CAR-T cells (hCART19) in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7575989/

Efficacy and safety of CD19 chimeric antigen receptor T cells ... Anti-CD19 CAR T-cell treatment is a new therapy for patients with relapsed and refractory B-cell lymphoma. Among the small sample size in this study, it ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/anti-cd19-car-cmv-specific-t-lymphocytes

Clinical Trials Using Anti-CD19-CAR CMV-specific T- ... Review the clinical trials studying anti-cd19-car cmv-specific t-lymphocytes on this list and use the filters to refine the results by age and location.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04213469

NCT04213469 | PD1-CD19-CART in Patients With r/r B- ... This study aims to evaluate the safety and efficacy of the treatment with PD1-CD19-CART. Detailed Description. PD1-CD19-CART is a kind of chimeric antigen T ...

5. withpower.com withpower.com/trial/phase-1-lymphoma-8-2023-6414c

CAR T-Cells + CMV-MVA Triplex Vaccine for Non- ... Research shows that combining CMV-specific T cells with CD19 CAR T cells can improve tumor control by enhancing the persistence and effectiveness of the T cells ...

6. nature.com nature.com/articles/s41421-023-00625-0

Safety and feasibility of anti-CD19 CAR T cells expressing ... In this study, we developed a novel CAR-T therapy for patients with R/R LBCL by engineering CD19-specific CAR-T cells to secrete IL-7 and CCL19 ...

7. jitc.bmj.com jitc.bmj.com/content/10/1/e003461

Large-scale manufacturing and characterization of CMV ... We demonstrated the feasibility of our large-scale platform for generating CMV-CD19CAR T cells for clinical application.