CAR-T Cells for Non-Hodgkin's Lymphoma

Overseen By UCSF HDFCCC Cancer Immunotherapy Program

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called CAR-T cells, which are specially modified immune cells designed to fight cancer. The focus is on non-Hodgkin's lymphoma, particularly types like Burkitt lymphoma, Marginal Zone Lymphoma, and Waldenström Macroglobulinemia. The goal is to determine if this treatment is safe and can be administered to patients who haven't responded to other therapies. Individuals with one of these lymphoma types who have not found success with other treatments might be suitable candidates for this study. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

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

Research has shown that a treatment called anti-CD19 CAR-T cells holds promise for various types of non-Hodgkin's lymphoma. This treatment has been particularly effective for aggressive large B-cell lymphoma that resists other treatments. While generally well-tolerated, some possible side effects require attention.

In studies, some patients experienced side effects, including fever, low blood pressure, or neurological effects like confusion or headaches. However, many patients managed these side effects with medical assistance.

Since this treatment is already in human trials, some initial safety information is available, but it remains under close observation. As a Phase 1 trial, the primary goal is to assess safety, so researchers will carefully monitor participants for any side effects or reactions to the treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CAR-T cell therapy for Non-Hodgkin's Lymphoma because it offers a unique approach that differs from traditional treatments like chemotherapy and targeted drugs. Unlike these standard treatments, which often target cancer cells broadly, CAR-T therapy uses genetically engineered T-cells to specifically target and attack cancer cells expressing the CD19 protein. This personalized approach can potentially lead to more precise and effective elimination of cancer cells with fewer side effects. Additionally, CAR-T therapy has shown promise in quickly reducing tumor size and maintaining remission over long periods, which is a significant advancement in treating aggressive forms of lymphoma.

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

Studies have shown that anti-CD19 CAR-T cells can be very effective against certain types of non-Hodgkin's lymphoma, a kind of blood cancer. In this trial, participants will receive anti-CD19 CAR-T cells, which have shown promise in previous research. Specifically, patients with Waldenström Macroglobulinemia, a type of this cancer, experienced complete responses, meaning their cancer became undetectable, after receiving CD19-targeting therapies. Research also shows that this treatment works well for patients who have not had success with other treatments. The treatment targets CD19, a protein on the surface of cancerous B cells, helping the body's immune system find and destroy them. Early findings suggest that these CAR-T cells can be very successful and have manageable side effects. ^{1 4 6 7 8}

Who Is on the Research Team?

C. Babis Andreadis, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Dose Expansion: Burkitt, Marginal Zone, or Waldenström Macroglobulinemia ONLY (CAR-T Therapy) Experimental Treatment 3 Interventions

Participants with Burkitt lymphoma, or Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM) will undergo Apheresis (1 day) to collect autologous lymphocytes/ mononuclear cells as per University of California, San Francisco (UCSF) institutional practices. CAR-T cell manufacturing (estimated \~13-14 days), during which participants will receive a lymphodepleting regimen of immunosuppressive chemotherapy (Cyclophosphamide 300 mg/m2/IV and fludarabine 30 mg/m2 /IV) followed by the infusion of the maximum tolerated dose of CAR-T cells established in the dose escalation phase, targeting CD19 over 5-30 minutes. Participants will be followed up 30 days after infusion, for up to 12 months, if the participant in continued remission, and for survival up to 15 years.

Group II: CLOSED TO ENROLLMENT: Dose escalation (CART-T Therapy) Experimental Treatment 0 Interventions

Participants will undergo Apheresis (1 day) to collect autologous lymphocytes/ mononuclear cells as per University of California, San Francisco (UCSF) institutional practices. CAR-T cell manufacturing (estimated \~13-14 days), during which participants will receive a lymphodepleting regimen of immunosuppressive chemotherapy (Cyclophosphamide 300 mg/m2/IV and fludarabine 30 mg/m2 /IV) followed by the infusion of CAR-T cells at an initial dose of 5 x 10\^5 cells/kg, targeting CD19 over 5-30 minutes. Participants will be followed up 30 days after infusion, for up to 12 months, if the participant in continued remission, and for survival up to 15 years.

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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CD19 CAR-NK is a targeted high- ... Single-agent CD19 CAR-NK cell therapy achieved a complete response in third-line Waldenstrom macroglobulinemia (WM), a type of non-Hodgkin ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12466217/

real-world outcomes of CD19 CAR T-cell therapy in ... The outcome of relapsed/refractory TriNHL is better than that of relapsed/refractory de novo LBCL. The toxicity profile of CAR T cells in ...

3. ajmc.com ajmc.com/view/two-patients-with-non-hodgkin-waldenstrom-lymphoma-see-complete-responses-with-cd19-car-nk-immunotherapy-immunitybio-reports

Two Patients With Non-Hodgkin Waldenstrom Lymphoma ... ImmunityBio's study reveals promising results for chemotherapy-free CD19 CAR NK cell therapy in treating Waldenström macroglobulinemia, offering

4. onclive.com onclive.com/view/cd19-t-hank-leads-to-complete-responses-in-waldenstrom-macroglobulinemia

CD19 t-haNK Leads to Complete Responses in ... CD19 t-haNK demonstrated complete responses in 2 patients with heavily pretreated Waldenstrom macroglobulinemia.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497124011595

High efficacy of CD19 CAR T cells in patients with ... Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8261235/

A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin ... However, the clinical effect of anti-CD19 CAR-T cells in patients with ALL seems more significant than in patients with lymphoma. In many patients with lymphoma ...

7. ashpublications.org ashpublications.org/bloodadvances/article/9/18/4693/537083/TRANSCAR-real-world-outcomes-of-CD19-CAR-T-cell

real-world outcomes of CD19 CAR T-cell therapy in relapsed ... Anti-CD19 chimeric antigen receptor (CAR) T cells have shown impressive results in the treatment of relapsed/refractory (R/R) aggressive large B-cell lymphoma ( ...

8. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05360238?cond=MB-106&draw=2&rank=1

Study to Assess Safety, Tolerability and Efficacy of MB-106 ... This is a multicenter, Phase 1/2, open-label, non-randomized study of MB-106 in patients ≥18 years of age with selected CD20-expressing malignancies.