CAR-T Cell Therapy for B-Cell Lymphoma

Overseen by Natalie S. Grover

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must be taking: Anti-CD20 antibodies

Must not be taking: Corticosteroids, CYP1A2 inhibitors

Disqualifiers: Pregnancy, HIV, HBV, HCV, others

No Placebo Group

Approved in 6 Jurisdictions

Trial Summary

What is the purpose of this trial?

This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results have shown that subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome and neurotoxicity. In this study, to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells have a safety switch that, when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome and or neurotoxicity as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome and/or neurotoxicity. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome and/or neurotoxicity, but still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma. The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable in patients with relapsed/refractory B-cell lymphoma, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong inhibitors of CYP1A2 or chemotherapy within specific timeframes before the treatment. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment iC9-CAR19 T cells for B-Cell Lymphoma?

Research shows that anti-CD19 CAR T-cell therapy, which is similar to iC9-CAR19 T cells, has been effective in treating aggressive B-cell lymphomas, leading to long-term remissions in patients who did not respond to other treatments. ^{1 2 3 4 5}

Is CAR-T cell therapy safe for humans?

CAR-T cell therapy, including treatments like iC9-CAR19 T cells, has been generally well tolerated in clinical trials for B-cell malignancies. Some patients experienced side effects like cytokine release syndrome (a reaction causing fever and low blood pressure) and neurotoxicity (nerve damage), but these were often mild. Safety data from trials show that while there are risks, the therapy is considered safe for many patients. ^{1 3 6 7 8}

What makes iC9-CAR19 T cells unique for treating B-cell lymphoma?

iC9-CAR19 T cells are a type of CAR T-cell therapy that targets CD19 on B-cells, offering a novel approach for patients with aggressive B-cell lymphomas that do not respond to traditional chemotherapy. This treatment is unique because it uses genetically modified T-cells to specifically attack cancer cells, potentially leading to long-lasting remissions in cases where other treatments have failed. ^{1 2 4 9 10}

Research Team

Natalie S. Grover

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults over 18 with certain types of B-cell lymphoma or leukemia who have tried at least two other treatments without success. It's not for pregnant women, those with severe hepatitis B, or HIV/HTLV/HCV infections. Participants must be willing to use birth control and have a Karnofsky score above 60%, indicating they can care for themselves.

Inclusion Criteria

Measurable or assessable disease by specified criteria

Women of childbearing potential must follow contraceptive measures

I have received treatments specific to my type of lymphoma.

Exclusion Criteria

Pregnant or lactating subjects

History of intolerance to fludarabine

I do not have an active infection with any major viruses.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Procurement

Peripheral blood is collected for cell procurement, and leukapheresis may be performed if necessary

1-2 weeks

Up to 3 visits (in-person)

Lymphodepleting Regimen

Subjects receive a cytoreductive regimen of bendamustine and fludarabine or cyclophosphamide and fludarabine

3 days

3 visits (in-person)

Treatment

Administration of iC9-CAR19 T cells post lymphodepletion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• iC9-CAR19 T cells (CAR T-cell Therapy)

Trial Overview The study tests iC9-CAR19 T cells designed to target CD19 on cancer cells, combined with chemotherapy drugs like Bendamustine and Fludarabine. If severe side effects occur, AP1903 is used to activate a 'safety switch' in the T cells to reduce their activity.

Participant Groups

Group I: Single Arm iC9.CAR19 T cells Experimental Treatment 5 Interventions

The safety of iC9-CAR19 cells will be investigated using the 3+3 design. Dose level (DL) Dose (#transduced cells/kg) -1 1 x 10\^5 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. Lymphodepleting chemotherapy of IV bendamustine 70 mg/m2 and IV fludarabine 30 mg/m2/day for 3 consecutive days will be given within 2-14 days prior to cell infusion. AP1903 (0.4 mg/kg), a dimerizing agent to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).

Group II: Expansion Cohort iC9-CAR19 cells Experimental Treatment 5 Interventions

After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects).

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

Dr. Shelley Earp

UNC Lineberger Comprehensive Cancer Center

Chief Medical Officer since 2018

MD from Johns Hopkins Medical School

Dr. Robert L. Ferris

UNC Lineberger Comprehensive Cancer Center

Chief Executive Officer

PhD in Immunology and MD from Johns Hopkins Medical School; Bachelor's in Chemistry from UNC-Chapel Hill

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

UNC Chapel Hill University Cancer Research Fund

Collaborator

Trials

1

Recruited

30+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

The V Foundation

Collaborator

Trials

10

Recruited

320+

Findings from Research

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]

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]

Anti-CD19 CAR T cell therapy has shown promising results in treating advanced-stage B-cell malignancies, with some patients achieving long-term remissions after treatment, indicating its potential as a new standard therapy.

While the therapy demonstrates strong efficacy by specifically targeting CD19, some patients have experienced acute adverse effects linked to increased inflammatory cytokines, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Kochenderfer, JN., Rosenberg, SA.[2021]

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]

CD19 is a highly effective target for CAR T-cell therapies, showing significant responses in patients with relapsed B-cell malignancies, particularly chronic lymphocytic leukemia and acute lymphoblastic leukemia.

While treatment with CD19-CAR T cells can lead to severe systemic inflammatory reactions, these are generally reversible with proper medical care, highlighting the importance of monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-CAR trials. Ramos, CA., Savoldo, B., Dotti, G.[2022]

In a phase 1 study involving 12 pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the autologous CD19-CAR T-cell therapy was well tolerated, with low rates of cytokine release syndrome (6 patients) and neurotoxicity (3 patients).

75% of the patients achieved a minimal residual disease-negative complete response in the bone marrow, although higher disease burden before treatment was linked to more side effects and lower response rates, emphasizing the importance of pre-infusion disease status on treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Talleur, AC., Qudeimat, A., Métais, JY., et al.[2022]

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]

CAR-T-cell therapy has shown significant promise in treating relapsed or refractory B-cell malignancies, such as B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, by targeting specific antigens like CD19 and BCMA.

The review highlights both the efficacy and toxicity of CD19- and BCMA-targeted CAR-T-cell therapies, indicating that while these treatments can be effective, they also come with potential side effects that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Roex, G., Feys, T., Beguin, Y., et al.[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]

References

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

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

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

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

3. England pubmed.ncbi.nlm.nih.gov

Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. [2021]

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

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

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

CD19-CAR trials. [2022]

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

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. [2022]

7. 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]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Successful treatment of a case with synchronous follicular lymphoma and gastric adenocarcinoma with CD19 CAR T cells and literature review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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