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

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of intracerebroventricularly (ICV) administered CD19-chimeric antigen receptor (CAR) T cells in treating patients with primary central nervous system (CNS) lymphoma. CAR T cell therapy is 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, CD19, on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. ICV is an injection technique that delivers the CD19-CAR T cells directly into the cerebrospinal fluid (which flows in and around the hollow spaces of the brain and spinal cord, and the thin layers of tissue that cover and protect the brain and spinal cord) in the brain, through a surgically placed catheter. Giving CD19-CAR T cells ICV may be more effective at treating patients with primary CNS lymphoma than giving them via other methods.

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 CAR T-cell therapy generally safe for humans?

CAR T-cell therapy, including products like axicabtagene ciloleucel and tisagenlecleucel, has been approved for certain types of lymphoma, but it can cause side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are important considerations for the safe use of this therapy. ^{1 2 3 4 5}

How is CAR T-cell therapy for brain lymphoma different from other treatments?

CAR T-cell therapy for brain lymphoma is unique because it involves genetically engineered T-cells that target CD19, a protein on cancer cells, and can be delivered directly into the brain's fluid spaces (intracerebroventricularly) to effectively treat both brain and systemic lymphoma, unlike traditional treatments that may not reach the brain effectively. ^{3 5 6 7 8}

What data supports the effectiveness of this treatment for brain lymphoma?

Research shows that CAR T-cell therapies targeting CD19, like tisagenlecleucel, have been effective in treating other types of B-cell lymphomas, with some patients experiencing complete or partial responses. In a study with secondary CNS lymphoma patients, tisagenlecleucel showed activity in the brain without severe side effects, suggesting potential effectiveness for brain lymphoma. ^{2 5 7 9 10}

Research Team

Tanya Siddiqi, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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 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]

References

1. New Zealand 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. [2020]

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

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

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

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

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

Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. [2022]

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

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. [2023]

6. Switzerland 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. [2020]

8. United States 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. [2021]

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

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma. [2022]

10. England 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. [2023]