CAR T-Cell Therapy for Brain Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Dexamethasone

Disqualifiers: Autoimmune disease, Stroke, HIV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating brain lymphoma using CAR T-cell therapy, which modifies a patient's own T cells to better combat cancer cells. The trial seeks to determine the safest dose and understand any side effects when the treatment is injected directly into the brain's fluid. This approach may prove more effective for central nervous system lymphoma than other methods. Individuals who have not responded to other CNS lymphoma treatments might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works 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 does not specify if you need to stop taking your current medications. However, you cannot take more than 4mg/day of dexamethasone (a type of steroid) within 72 hours before certain procedures in the trial.

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

Research has shown that CD19-CAR T cells are generally safe for use in the central nervous system (CNS). Most patients tolerated the treatment well, with their immune systems responding as expected. In earlier studies, side effects were manageable, although some patients experienced inflammation, a common occurrence with treatments that activate the immune system.

This therapy involves modifying T cells to attack cancer cells and has been studied in various contexts. Delivering these cells directly into the brain is a new approach, but the overall safety of CD19-CAR T cell therapy in other settings provides some reassurance. However, since this study is in its early phase, it primarily focuses on understanding potential side effects and determining the right dose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for brain lymphoma, which typically involve chemotherapy, radiation, or targeted therapy, CD19-CAR T-cell therapy works by reprogramming a patient's own immune cells to target and destroy cancer cells. This treatment is particularly exciting because it harnesses the body's natural defenses, potentially offering a more precise attack on cancer with fewer side effects. Additionally, the delivery of CD19-CAR T cells directly into the cerebrospinal fluid (ICV) is innovative, aiming to enhance the treatment's effectiveness by reaching the cancer cells in the brain more directly. Researchers are hopeful that this approach could lead to more effective and longer-lasting remissions for patients with brain lymphoma.

What evidence suggests that this treatment might be an effective treatment for brain lymphoma?

Research has shown that CD19-CAR T cell therapy, which participants in this trial will receive, could be promising for treating central nervous system (CNS) lymphoma. In a study with patients who had primary CNS lymphoma, these specially engineered T cells effectively found and attacked cancer cells. They are designed to recognize and destroy cells with a specific protein called CD19, found on many lymphoma cancer cells. Some early results indicated that patients experienced tumor shrinkage after receiving this treatment. This therapy is a new approach and is still under extensive study, but the initial findings are encouraging. ^{1 2 3 6 7}

Who Is on the Research Team?

Tanya Siddiqi, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults (18+) with primary CNS lymphoma, measurable disease, and CD19+ tumor expression can join this trial. They must have tried certain treatments like high-dose methotrexate or cytarabine without success. Participants need to be in fair health (ECOG 0-2), able to consent, and agree to use birth control. Exclusions include uncontrolled infections, active autoimmune diseases needing strong meds, HIV, hepatitis B/C infection, other cancers within the last 3 years (except some skin cancers), history of stroke or bleeding disorders.

Inclusion Criteria

My recent heart test shows no serious issues needing further checks or treatment.

Patients with Gilbert syndrome may be included if their total bilirubin is =< 3.0 x upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN

Total serum bilirubin =< 2.0 mg/dL (within 14 days of signing the screening and leukapheresis consent)

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition or other agents used in this study

I am still experiencing side effects from my previous cancer treatment.

I haven't had a stroke or brain bleed in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo catheterization, leukapheresis, and receive CD19-CAR T cells ICV. They may also receive fludarabine and cyclophosphamide IV. Imaging and sample collection are conducted throughout the trial.

6-8 weeks

Multiple visits for treatment and monitoring

Follow-up

Participants are monitored for safety, effectiveness, and adverse events, including disease response and progression-free survival.

Up to 15 years

Regular follow-up visits

Long-term Monitoring

Participants are monitored for overall survival and long-term adverse events.

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• CD19-CAR T Cells

Trial Overview This phase I trial is testing a new way to deliver CAR T-cell therapy for CNS lymphoma by injecting modified immune cells directly into the brain's fluid via a catheter. It aims to find out the safest dose and observe side effects when these engineered T-cells target cancer cells expressing CD19 protein.

How Is the Trial Designed?

Group I: Treatment (leukapheresis, CD19-CAR T cells) Experimental Treatment 11 Interventions

Patients may undergo catheterization, undergo leukapheresis, may receive fludarabine IV and cyclophosphamide IV, and receive CD19-CAR T cells ICV on study. Patients also undergo MRI, PET, CT, collection of blood samples, and CSF aspiration throughout the trial, and lumbar puncture as clinically indicated.

CD19-CAR T Cells is already approved in European Union, United States for the following indications:

Approved in European Union as Tisagenlecleucel for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma

Approved in United States as Tisagenlecleucel for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Axicabtagene ciloleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Axicabtagene ciloleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Tecartus for:

• Mantle cell lymphoma

Approved in United States as Tecartus for:

• Mantle cell lymphoma
• Acute lymphoblastic leukemia

Approved in European Union as Brexucabtagene autoleucel for:

• Mantle cell lymphoma

Approved in United States as Brexucabtagene autoleucel for:

• Mantle cell lymphoma

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

Axicabtagene ciloleucel (axi-cel) is an FDA-approved CAR T-cell therapy specifically designed to target CD19, showing promise in treating relapsed or refractory aggressive non-Hodgkin's lymphomas, including diffuse large B-cell lymphoma.

While axi-cel has demonstrated significant efficacy in clinical trials (ZUMA-1 Phase I and II), it is associated with potential toxicities such as cytokine release syndrome and neurotoxicity, which pose challenges for safe administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma. Jain, MD., Bachmeier, CA., Phuoc, VH., et al.[2020]

CAR T-cell therapy, particularly with anti-CD19 targeting, has shown significant effectiveness in treating aggressive B-cell non-Hodgkin's lymphoma (NHL), leading to long-term remissions in patients with diffuse large B-cell lymphoma (DLBCL) who have not responded to other treatments.

Two CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved by the FDA for refractory DLBCL, while a third product, liso-cel, is showing promising results in ongoing trials, although potential side effects like cytokine-release syndrome and neurotoxicity are important considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Chavez, JC., Bachmeier, C., Kharfan-Dabaja, MA.[2020]

The three CAR-T cell therapies (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) show promising efficacy in treating large B cell lymphoma, with overall response rates of nearly 70% and complete response rates exceeding 50% across 33 studies involving 2,172 patients.

However, axicabtagene ciloleucel and tisagenlecleucel are associated with significant risks of severe neurotoxicity and life-threatening cytokine release syndrome, necessitating careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis. Meng, J., Wu, X., Sun, Z., et al.[2022]

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 111 patients with refractory large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated a high objective response rate of 82%, with 54% achieving a complete response, indicating its efficacy as a treatment option.

The treatment was associated with significant adverse events, including neutropenia in 78% of patients and neurologic events in 28%, highlighting the need for careful monitoring of safety during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. Neelapu, SS., Locke, FL., Bartlett, NL., et al.[2023]

Intracerebroventricular (ICV) delivery of CD19-targeted CAR T cells was found to completely and durably eliminate both central nervous system (CNS) and systemic lymphoma in a mouse model, while intravenous (IV) delivery did not achieve the same results.

The enhanced efficacy of ICV-delivered CAR T cells is attributed to their conditioning by cerebrospinal fluid, which improves their anti-lymphoma activity and memory function, suggesting a promising new treatment strategy for B-cell malignancies with CNS involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma. Wang, X., Huynh, C., Urak, R., et al.[2022]

In a study of 75 patients with large B-cell lymphoma receiving CAR T-cell therapy, high pretreatment levels of the cytokine IL6 were linked to severe immune-mediated toxicities like cytokine release syndrome (CRS) and neurotoxicity (NT).

The research also found that certain gene expressions in tumor biopsies indicated a proinflammatory tumor microenvironment, which may increase the risk of toxicity, suggesting that personalized management strategies could help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel. Faramand, R., Jain, M., Staedtke, V., et al.[2021]

In a study of 45 patients with active CNS lymphoma receiving CAR T-cell therapy, 68.9% showed a CNS response, with 40% achieving a complete response lasting an average of 11.4 months, indicating the therapy's efficacy in this challenging population.

While CAR T-cell therapy demonstrated a favorable safety profile, mild to severe neurotoxicity (ICANS) occurred in 42.2% and 15.6% of transfusions, respectively, with higher risks associated with secondary CNS lymphoma and certain pre-treatment factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells. Karschnia, P., Arrillaga-Romany, IC., Eichler, A., et al.[2023]

In the phase II JULIET trial, the CAR T-cell therapy tisagenlecleucel targeting CD19 demonstrated durable responses in patients with relapsed and refractory diffuse large B-cell lymphoma, with 32% achieving complete responses at 3 months.

The efficacy remained stable at 6 months, with 30% of patients still showing complete responses, indicating the potential long-term effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Value in Using CAR T Cells for DLBCL. [2019]

In a study of 8 patients with secondary CNS lymphoma treated with CAR T cells targeting CD19, no patients experienced severe neurotoxicity, indicating a favorable safety profile for this therapy in this specific population.

Despite the exclusion of CNS involvement in earlier trials, the CAR T cells showed signs of expansion and activity within the CNS, suggesting potential efficacy for treating CNS lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Frigault, MJ., Dietrich, J., Martinez-Lage, M., et al.[2022]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cd19car-cd28-cd3zeta-egfrt-expressing-tcm-enriched-t-lymphocytes

Clinical Trials Using CD19CAR-CD28-CD3zeta-EGFRt ... Review the clinical trials studying cd19car-cd28-cd3zeta-egfrt-expressing tcm-enriched t-lymphocytes on this list and use the filters to refine the results ...

2. ctsearchsupport.org ctsearchsupport.org/clinical-trials/intracerebroventricular-administration-of-cd19-car-t-cells-cd19car-cd28-cd3zeta-egfrt-expressing-tcm-enriched-t-lymphocytes-for-the-treatment-of-primary-central-nervous-system-lymphoma

CAR T cells (CD19CAR-CD28-CD3zeta-EGFRt-expressing ... CAR T cells (CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes) to treat central nervous system (CNS) lymphoma ; Ages: 18 and ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34492703/

CD19-directed CAR T-cell therapy for treatment of ... - PubMed Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12571805/

Biomarkers for predicting CAR-T cell therapy outcomes in B ... This innovative strategy involves genetically modifying a patient's autologous T cells to target CD19-positive malignant cells (4), achieving ...

5. molecular-cancer.biomedcentral.com molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01755-5

CAR T-Cell therapy for the management of mantle cell ... USFDA has approved brexucabtagene autoleucel (Tecartus, KTE-X19), a novel CAR T-cell therapy to be used in patients with MCL who have not responded to previous ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12557894/

Challenges and limitations of chimeric antigen receptor T-cell ... ... CAR-T cells demonstrated a favorable safety profile and robust immune activation within the central nervous system (CNS). Elevated levels of ...

7. researchgate.net researchgate.net/publication/391529633_Outcomes_of_Brexucabtagene_Autoleucel_in_RelapsedRefractory_Acute_Lymphoblastic_Leukemia_Patients_with_CNS_Involvement

Outcomes of Brexucabtagene Autoleucel in Relapsed/ ... In this retrospective multicenter analysis, we investigated the safety and efficacy of brexu-cel in CNS B-ALL patients utilizing data from the ...