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 phase I trial studies the safety and feasibility of cytomegalovirus (CMV) specific CD19-chimeric antigen receptor (CAR) T cells in combination with the CMV-modified vaccinia Ankara (MVA) triplex vaccine following lymphodepletion in treating patients with intermediate or high grade B-cell non-Hodgkin lymphoma (NHL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refectory). CAR T cells are a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added in the laboratory. The special receptor is called CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. Vaccines such as CMV-MVA triplex are made from gene-modified viruses and may help the body build an effective immune response to kill cancer cells. Giving CMV-specific CD19-CAR T-cells plus the CMV-MVA triplex vaccine may help prevent the cancer from coming back.

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 the CAR T-Cells + CMV-MVA Triplex Vaccine treatment generally safe for humans?

CAR T-cell therapy, including those targeting CD19, can cause side effects such as infections, cytokine release syndrome (a severe immune reaction), and other organ-related toxicities. While these treatments can be effective, they come with risks that are still being studied, especially regarding long-term safety. ^{1 2 3 4 5}

What makes the CAR T-Cells + CMV-MVA Triplex Vaccine treatment unique for Non-Hodgkin's Lymphoma?

This treatment is unique because it combines CAR T-cells, which are engineered to target cancer cells, with a CMV-MVA Triplex Vaccine that boosts the immune system's response to cytomegalovirus (CMV), potentially enhancing the effectiveness and persistence of the CAR T-cells in fighting lymphoma. ^{2 6 7 8 9}

What data supports the effectiveness of the treatment CAR T-Cells + CMV-MVA Triplex Vaccine for Non-Hodgkin's Lymphoma?

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. Additionally, CMV-specific T cell therapy has been effective in restoring immunity in patients with CMV infections, suggesting potential benefits in boosting the immune response in cancer treatment. ^{2 10 11 12 13}

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Large-scale manufacturing and characterization of CMV-CD19CAR T cells. [2022]

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

CMV-specific T cell therapy. [2007]

3. United States 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. [2022]

4. Japan 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. [2022]

5. China pubmed.ncbi.nlm.nih.gov

Loop CD20/CD19 CAR-T cells eradicate B-cell malignancies efficiently. [2023]

6. Denmark pubmed.ncbi.nlm.nih.gov

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. [2020]

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

K562-Derived Whole-Cell Vaccine Enhances Antitumor Responses of CAR-Redirected Virus-Specific Cytotoxic T Lymphocytes In Vivo. [2021]

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

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

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

Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. [2023]

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

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation. [2023]

12. United States 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. [2023]

13. England 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. [2022]