CAR-T Cells for Non-Hodgkin's Lymphoma

Overseen By Laurel Brechtel

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: C. Babis Andreadis

Must not be taking: Corticosteroids

Disqualifiers: Active malignancy, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 2

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will assess safety and feasibility of infusing genetically modified autologous T cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen Cluster of Differentiation 19 (CD19)

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use corticosteroids within 7 days before the infusion, except for preventing nausea during chemotherapy.

What data supports the effectiveness of the treatment for Non-Hodgkin's Lymphoma?

Research shows that CD19-directed CAR T-cell therapy is effective for patients with relapsed or hard-to-treat B-cell non-Hodgkin lymphoma, with encouraging response rates observed in various studies. ^{1 2 3 4 5}

Is CAR-T cell therapy safe for humans?

CAR-T cell therapy, including anti-CD19 CAR-T cells, has been shown to be effective but can have side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are generally manageable with proper medical care, but ongoing research is needed to better understand and reduce these risks. ^{6 7 8 9 10}

How does the treatment with anti-CD19 CAR-T cells differ from other treatments for non-Hodgkin's lymphoma?

Anti-CD19 CAR-T cell therapy is unique because it uses the patient's own immune cells, which are modified to specifically target and destroy cancer cells in non-Hodgkin's lymphoma. This approach is different from traditional treatments like chemotherapy, as it harnesses the body's immune system to fight the cancer. ^{4 11 12 13 14}

Research Team

C. Babis Andreadis, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults with certain types of B-cell Non-Hodgkin Lymphoma that have relapsed or didn't respond to previous treatments can join. They should not be eligible for stem cell transplant, must have tried at least two systemic therapies, and still show CD19 positive cells. Key organ functions need to be within normal ranges, they shouldn't have other active cancers or severe illnesses, and women who can get pregnant must agree to use contraception for a year after treatment.

Inclusion Criteria

My lymphoma shows up on PET scans.

My B-cell NHL subtype fits the specific treatment history criteria.

I am not pregnant and agree to use birth control for a year after treatment.

Exclusion Criteria

Specific criteria for eligibility for infusion of investigational product

I am HIV positive.

Pregnancy or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Apheresis and CAR-T Cell Manufacturing

Participants undergo apheresis for collection of autologous peripheral blood mononuclear cells, followed by CAR-T cell manufacturing

Approximately 13-14 days

1 visit (in-person) for apheresis

Lymphodepleting Chemotherapy

Participants receive 3 days of immunosuppressive chemotherapy with cyclophosphamide and fludarabine

3 days

CAR-T Cell Infusion

Participants receive a single infusion of anti-CD19 CAR-T cells

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, disease status, and survival

12 months

Long-term Follow-up

Participants are followed for long-term safety and survival

Up to 15 years

Treatment Details

Interventions

• anti-CD19 CAR-T cells
• Cyclophosphamide
• Fludarabine

Trial Overview The trial is testing genetically modified T cells that target CD19 on the surface of B cells. Patients will receive Cyclophosphamide and Fludarabine as part of the preparation before getting these anti-CD19 CAR-T cells infused into their bloodstream.

Participant Groups

Group I: Treatment Regimen Experimental Treatment 3 Interventions

Apheresis (1 day): Autologous lymphocytes/ mononuclear cell collection will be collected through standard apheresis procedures as per University of California, San Francisco (UCSF) institutional practices CAR-T cell manufacturing (estimated \~13-14 days) Lymphodepleting chemotherapy: 3 days of immunosuppressive chemotherapy. Cyclophosphamide given at a dose of 300 mg/m2/IV and fludarabine given at 30 mg/m2 /IV on days -5, -4, and -3. CAR-T cell infusion (1 day): The infusion of CAR-T cells targeting CD19 will occur over 5-30 minutes.

Who Is Running the Clinical Trial?

C. Babis Andreadis

Lead Sponsor

Trials

5

Recruited

130+

University of California, Davis

Collaborator

Trials

958

Recruited

4,816,000+

Findings from Research

CD19-directed CAR T-cell therapy has shown promising results in treating relapsed/refractory B-cell non-Hodgkin lymphoma, with 30-40% of patients achieving durable responses in pivotal phase I/II trials, leading to FDA and EMA approvals for specific therapies.

Despite its effectiveness, the therapy is associated with significant toxicities, such as cytokine release syndrome and neurotoxicity, which can limit its use and present challenges in patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-directed CAR T-cell therapy in B-cell NHL. Kersten, MJ., Spanjaart, AM., Thieblemont, C.[2021]

CAR.λ T cells effectively target and kill Igλ+ lymphoma cells and chronic lymphocytic leukemia (CLL) cells, showing similar antitumor activity to the established CAR.CD19 T cells in both laboratory and animal models.

Importantly, CAR.λ and CAR.κ T cells selectively deplete only the corresponding light chain-expressing normal B cells, preserving the other type, which suggests a safer approach with minimal impact on the immune system's ability to produce antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells. Ranganathan, R., Shou, P., Ahn, S., et al.[2022]

CD19CAR T cells have shown promising results in treating aggressive B-lineage cancers, but their effectiveness can be limited by the loss of the targeted CD19 antigen, leading to treatment failure.

The newly developed adapter CAR T cell technology (AdCAR) allows for multitargeting of different antigens, such as CD20 and CD22, which can enhance the anti-cancer activity and potentially overcome issues related to antigen loss in lymphoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. Atar, D., Mast, AS., Scheuermann, S., et al.[2022]

Cellular therapies, including CAR T cells and allogeneic stem cell transplantation, have shown significant effectiveness in treating aggressive non-Hodgkin lymphomas, particularly in patients with poor prognoses.

The article discusses the clinical approach to selecting patients for CD19-directed CAR T cell therapy, emphasizing its growing importance in lymphoma management and the potential of newer cell therapies to enhance immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy with cells. Chong, EA., Porter, DL.[2023]

Anti-CD19 CAR-T therapy has been approved for patients with relapsed/refractory diffuse large B cell lymphoma, showing promising clinical outcomes based on recent trials like ZUMA-1, JULIET, and TRANSCEND NHL-001.

Healthcare providers need to understand the indications, potential toxicities, and limitations of this therapy to effectively manage patient referrals and treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma. Havard, R., Stephens, DM.[2020]

Anti-CD19 CAR-modified T cells have demonstrated a 48% overall response rate in treating B-cell malignancies, with complete responses observed in 24% of patients across six phase I clinical trials involving 50 patients.

The study found that conditioning chemotherapy significantly improves progression-free survival (PFS), making it a crucial factor for enhancing the efficacy of CAR T-cell therapy, while the treatment was generally well tolerated with temporary adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. Zhu, Y., Tan, Y., Ou, R., et al.[2022]

In a study of 11 patients with relapsed and refractory B-cell lymphoma, anti-CD19 CAR T-cell therapy achieved a remarkable overall response rate of 100%, with a complete remission rate of 63.6% after 3 months, indicating its high efficacy as a treatment option.

The therapy was generally safe, with a 36.4% incidence of Grade 2 cytokine release syndrome and one case of Grade 3 CAR T-cell-related encephalopathy syndrome, suggesting manageable adverse reactions in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study. Huang, C., Wu, L., Liu, R., et al.[2022]

Chimeric antigen receptor (CAR)-T cell therapy, specifically targeting CD19, has shown promising results in treating non-Hodgkin lymphomas (NHLs) resistant to standard therapies, leading to FDA and EMA approvals for tisagenlecleucel and axicabtagene ciloleucel.

While CAR-T cell therapy can cause significant adverse events like cytokine release syndrome and neurological toxicity, these effects are manageable with proper medical support, highlighting the importance of trained teams in administering this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. Hopfinger, G., Jäger, U., Worel, N.[2020]

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]

Adoptive cellular immunotherapy using anti-CD19 CAR-T cells has significantly improved treatment outcomes for patients with relapsed or refractory B cell lymphomas, leading to durable remissions, with two products already FDA-approved and a third in large clinical trials.

Despite their effectiveness, CAR-T cell therapies can cause serious side effects like infections and cytokine release syndrome, highlighting the need for better understanding of these toxicities and strategies to mitigate them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in CAR-T Cell Therapy for Non-Hodgkin Lymphoma. Kallam, A., Vose, JM.[2020]

Anti-CD19 CAR T-cell therapy has demonstrated significant clinical activity in treating B-cell non-Hodgkin lymphoma (NHL), with objective response rates ranging from 50-83% for relapsed diffuse large B-cell lymphoma (DLBCL), 83-93% for follicular lymphoma (FL), and 93% for mantle cell lymphoma (MCL).

This therapy represents a promising treatment option for patients with poor-risk refractory B-cell NHLs, highlighting its potential efficacy in difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. Chavez, JC., Yassine, F., Sandoval-Sus, J., et al.[2022]

CD19-directed CAR T-cell therapy has significantly transformed the treatment approach for aggressive B-cell non-Hodgkin lymphoma, offering new hope for patients.

There are currently three commercially available CAR T-cell therapies targeting CD19, indicating a growing acceptance and application of this innovative immunotherapy in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy for Relapsed/Refractory Aggressive Large B-Cell Lymphoma. Gideon, J.[2023]

In a phase I study involving 10 patients with refractory B-cell non-Hodgkin's lymphoma, the anti-CD19 CAR T cell therapy JWCAR029 achieved a remarkable overall response rate of 100%, with 66.7% of evaluable patients reaching complete remission.

While JWCAR029 was effective, it was associated with significant adverse events, including 100% incidence of neutropenia and grade 1 cytokine release syndrome in all patients, highlighting the importance of monitoring for side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma. Yan, ZX., Li, L., Wang, W., et al.[2020]

Adoptive T cell therapy using anti-CD19-CAR5-T cells, which secrete anti-PD-L1, showed improved effectiveness in killing aggressive B cell lymphomas compared to traditional anti-CD19-CAR-T cells, especially at low effector-to-target ratios.

The study demonstrated that anti-CD19-CAR5-T cells not only proliferated better but also enhanced cytotoxicity against CD19+/PD-L1high tumor cells, suggesting a promising new approach for treating difficult-to-treat B cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T cells secreting anti-PD-L1 single-chain variable fragment attenuate PD-L1 mediated T cell inhibition. Yuti, P., Wutti-In, Y., Sawasdee, N., et al.[2022]

References

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

CD19-directed CAR T-cell therapy in B-cell NHL. [2021]

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

CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. [2022]

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

Immunotherapy with cells. [2023]

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

Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. [2022]

7. China pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study. [2022]

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

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Recent Advances in CAR-T Cell Therapy for Non-Hodgkin Lymphoma. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. [2022]

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

CAR T-Cell Therapy for Relapsed/Refractory Aggressive Large B-Cell Lymphoma. [2023]

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

Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma. [2020]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T cells secreting anti-PD-L1 single-chain variable fragment attenuate PD-L1 mediated T cell inhibition. [2022]