CAR-T Cell Therapy for Lymphoma

(CABAL2 Trial)

Recruiting at 1 trial location

Overseen By Premal Lulla, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Systemic corticosteroids

Disqualifiers: Pregnant, Cardiac disease, Infections, others

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

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

90 Participants Needed

Trial Summary

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 participate if you have used certain investigational drugs or therapies recently, or if you are currently using high-dose corticosteroids.

What data supports the effectiveness of the treatment C7R.CD30.CAR-EBVST cells for lymphoma?

Research shows that modifying T-cells with a C7R receptor can enhance their ability to fight tumors, as seen in Epstein-Barr virus-specific T-cells that controlled lymphoma more effectively in a mouse model. Additionally, CAR T-cell therapy, which is part of this treatment, has been effective in treating various types of lymphoma, including Hodgkin lymphoma. ^{1 2 3 4 5}

Is CAR-T cell therapy generally safe for humans?

CAR-T cell therapy can cause serious side effects, including cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects can lead to complications like infections or bleeding, and in some cases, they can be life-threatening. ^{6 7 8 9 10}

How is the C7R.CD30.CAR-EBVST cell treatment different from other lymphoma treatments?

This treatment is unique because it combines a chimeric antigen receptor (CAR) targeting CD30 with Epstein-Barr virus-specific T-cells (EBVSTs) enhanced by a constitutively active IL7 receptor (C7R), which improves the persistence and expansion of the T-cells, potentially leading to better control of lymphoma. ^{1 2 3 5 11}

What is the purpose of this trial?

This study involves patients that have a cancer called diffuse large B cell lymphoma (DLBCL), Natural killer/T-cell lymphoma (NKTL), or classical Hodgkin lymphoma (cHL) (referred to collectively as lymphoma). Patients' lymphoma has come back or not gone away after treatment. A previous research study at Baylor combined two ways of fighting disease: antibodies and T cells. Antibodies are proteins that bind to bacteria, viruses and other foreign substances to prevent disease. T-cells are special infection-fighting white blood cells that can kill tumor cells or cells infected with bacteria and viruses. Both have shown promise treating cancer, but neither has been strong enough to cure most patients. In the previous study, an antibody called anti-CD30 which is found on the surface of some T-cells and cancer cells, and had been used to treat lymphoma with limited success, was joined to the T-cells through a process called gene transfer, resulting in CD30.CAR T cells. Another study saw encouraging responses using CD30.CAR T cells made in a lab from a patients' own blood then injected back into the same patient to treat their lymphoma. These cells are termed 'autologous' because they're given back to the original patient. In an ongoing study, patients were treated with allogeneic CD30.CAR T cells, which are made from healthy donors instead of the patients. The use of allogenic cells avoids a lengthy manufacture time since the products are stored as a bank and available on demand. This ongoing trial has preliminarily shown promising clinical activity with no safety concerns. With the current study, investigators plan to extend the anti-cancer effects of the CD30.CAR T cell by attaching another molecule called C7R, which has made CAR T cells have deeper and longer anticancer effects in the laboratory. The aim is to study the safety and effectiveness of allogeneic banked CD30.CAR-EBVST cells that also carry the C7R molecule, to learn the side effects of C7R modified CD30.CAR-EBVST cells in lymphoma patients, and to see whether this therapy may help them. As an extra safety step, the C7R containing T cells will also have a marker called iC9. If a patient experiences intolerable side effects from the C7R T cells, they could receive a medication called 'rimiducid' that can eliminate the C7R containing T cells by binding iC9, thereby potentially resolving the side effects. While not yet FDA approved, rimiducid has been tested in patients before without bad side effects.

Research Team

Premal Lulla, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for patients with certain types of lymphoma, including diffuse large B cell, natural killer/T-cell, or classical Hodgkin lymphoma that has persisted or returned after treatment. Participants must meet specific health criteria not detailed here.

Inclusion Criteria

I have recovered from all major side effects of my previous chemotherapy.

I am between 12 and 75 years old.

My diagnosis is one of the specified types of lymphoma or I have a CD30-positive tumor.

Exclusion Criteria

My tumor is in a place where it could block my breathing if it gets bigger.

I am taking more than 10 mg/day of steroids.

I do not have any serious, uncontrolled infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for blood tests, physical examination, and imaging studies

Lymphodepletion Chemotherapy

Participants receive cyclophosphamide and fludarabine to reduce T cell count before infusion

1 week

1 visit (in-person)

Treatment

Participants receive C7R.CD30.CAR-EBVST cell infusion at one of four dose levels

4 weeks

Weekly visits for monitoring post-infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Visits at week 1, 2, 3, 4, 8, every 3 months for 1 year, every 6 months for 4 years, then yearly

Treatment Details

Interventions

• C7R.CD30.CAR-EBVST cells

Trial Overview The study tests C7R.CD30.CAR-EBVST cells on patients with lymphoma. It aims to improve upon previous CAR T cell therapies by using a modified version that may have longer and stronger effects against cancer.

Participant Groups

Group I: Treatment Phase Experimental Treatment 1 Intervention

Four dose levels will be evaluated based on safety data from our current study of CD30 CAR T cells. Cohorts of three patients will be enrolled at each dose level The dose is based on the number of CD.30 CAR-EBVT-expressing cells administered. The total number of dose levels evaluated will depend upon toxicities experienced. Dose level cohorts will be numbered sequentially. * Dose Level 1: 4 × 10\^7 C7R.CD30.CAR-EBVST cells * Dose Level 2: 1 × 10\^8 C7R.CD30.CAR-EBVST cells * Dose Level 3: 4 × 10\^8 C7R.CD30.CAR-EBVST cells * Dose Level 4: 8 × 10\^8 C7R.CD30.CAR-EBVST cells

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

The study demonstrated that modifying Epstein-Barr virus-specific T-cells (EBVSTs) with a constitutively active IL7 receptor (C7R) significantly enhances their expansion and anti-tumor activity, showing promise for treating EBV-associated malignancies.

C7R-EBVSTs exhibited improved lymphoma control in a mouse model compared to unmodified T-cells, leading to the initiation of a clinical trial for patients with refractory or relapsed EBV-positive lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Constitutive Interleukin-7 Cytokine Signaling Enhances the Persistence of Epstein-Barr Virus-Specific T-Cells. Sharma, S., Sauer, T., Omer, BA., et al.[2023]

CAR T-cell therapy is becoming a groundbreaking treatment for aggressive non-Hodgkin B-cell lymphoma, showing promise in improving patient outcomes.

The review discusses not only the efficacy of CAR T-cell therapy but also highlights the potential short- and long-term toxicities associated with the treatment, emphasizing the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. Hamilton, MP., Miklos, DB.[2023]

In a study involving 41 heavily pretreated patients with relapsed or refractory Hodgkin lymphoma, CD30-targeted CAR T-cell therapy demonstrated a high overall response rate of 72%, with 59% achieving complete responses after fludarabine-based lymphodepletion.

The therapy showed a favorable safety profile, with most adverse events being grade 3 or higher hematologic issues and only mild cytokine release syndrome observed, indicating that CAR T-cell therapy can be safely extended to treat Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. Ramos, CA., Grover, NS., Beaven, AW., et al.[2022]

CAR-T therapy is an innovative treatment that modifies T cells to target and attack cancer cells, such as those found in large B cell lymphoma.

In this case, a patient treated with CAR-T therapy for lymphoma developed myocarditis, highlighting a potential safety concern associated with this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case of Myocarditis After Chimeric Antigen Receptor T Cells With Intracardiac Lymphoma. Lee, DH., Jain, M., Lazaryan, A., et al.[2023]

The study reports on three patients with relapsed B-cell lymphomas who were treated with autologous T cells modified to express a CD20-targeted chimeric antigen receptor (CAR), showing promising clinical efficacy.

The treatment demonstrated a favorable safety profile, indicating that genetically modified T cells can be a viable option for patients with relapsed B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CARs and cancers: questions and answers. Brentjens, RJ.[2021]

In a study of 133 patients with relapsed or refractory lymphomas receiving CAR-T-cell therapy, severe cytopenias (neutropenia, anemia, and thrombocytopenia) were common, occurring in 71%, 30%, and 41% of patients, respectively, particularly in the early phase after treatment.

Severe cytopenias were linked to higher rates of infections and poorer survival outcomes, suggesting that better patient selection and management of cytokine release syndrome (CRS) could reduce these adverse effects and improve overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma. Zhou, J., Zhang, Y., Shan, M., et al.[2022]

In a study of 11,098 adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), 2.7% experienced severe neurologic adverse events (AEs) within 30 days of treatment, with a significant portion (36.4%) of those receiving CAR T-cell therapy affected.

Patients with neurologic AEs incurred an average of $71,982 higher healthcare costs, with CAR T-cell therapy users facing the highest costs, highlighting the financial burden associated with these severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Burden of Neurologic Toxicities Associated with Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma in the United States. Broder, MS., Ma, Q., Yan, T., et al.[2022]

In a study of 38 classical Hodgkin's Lymphoma (cHL) specimens, only 5.2% of Reed-Sternberg cells expressed both CD19 and CD30, indicating a limited population eligible for combined CAR T-cell therapy.

A patient treated with low doses of anti-CD19 and CD30 CAR T-cells did not experience severe adverse events and achieved long-term progression-free survival, suggesting that this approach may be safe and effective for high-risk relapsing/refractory cHL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19 and CD30 CAR T-Cell Immunotherapy for High-Risk Classical Hodgkin's Lymphoma. Xue, Y., Lai, X., Li, R., et al.[2022]

CAR-T cell therapy shows promise in treating relapsed or refractory malignancies, particularly in hematological cancers like acute B-cell lymphoblastic leukemia and B-cell lymphomas, with ongoing research into its application for solid tumors.

This systematic review aims to comprehensively assess the safety and efficacy of CAR-T cell therapy by analyzing various studies, focusing on outcomes such as complete response rates and adverse events, to better understand its potential risks and benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. Grigor, EJM., Fergusson, DA., Haggar, F., et al.[2019]

In a multi-center phase II clinical trial involving 12 patients with relapsed/refractory CD30+ lymphoma, the combination of anti-CD30 CAR-T therapy and PD-1 inhibitors resulted in a high overall response rate of 91.7%, with 50% of patients achieving complete remission.

The treatment demonstrated minimal toxicity, with only 4 patients experiencing cytokine release syndrome, and no cases of CAR-T-related encephalopathy syndrome, indicating a favorable safety profile alongside its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma. Sang, W., Wang, X., Geng, H., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Constitutive Interleukin-7 Cytokine Signaling Enhances the Persistence of Epstein-Barr Virus-Specific T-Cells. [2023]

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

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. [2023]

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

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Case of Myocarditis After Chimeric Antigen Receptor T Cells With Intracardiac Lymphoma. [2023]

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

CARs and cancers: questions and answers. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma. [2022]

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

Economic Burden of Neurologic Toxicities Associated with Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma in the United States. [2022]

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

CD19 and CD30 CAR T-Cell Immunotherapy for High-Risk Classical Hodgkin's Lymphoma. [2022]

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

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma. [2022]

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

Constant attack on T cell lymphomas. [2018]