Cell Therapy for Hodgkin's Lymphoma

Overseen By Catherine Cheng

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: UNC Lineberger Comprehensive Cancer Center

Disqualifiers: Major surgery, Investigational agents, Chemotherapy, others

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

Compensation: Varies

Number of Visits: Unknown

31 Participants Needed

Trial Summary

What is the purpose of this trial?

Despite the progress in the therapy, Hodgkin's Lymphoma (HL) remains fatal for more than 15% of patients. Even in patients who are cured, the morbidity of therapy is substantial and long-lasting. New therapeutic agents are required therefore not only to further reduce mortality but also to alleviate morbidity. The majority of HL express the CD30 antigens. CD30 expression is routinely used for the diagnosis of HL. Preclinical observations support CD30 as a viable target of CAR-T therapy. This phase Ib/II study was conducted based on these observations. The purpose of this study is to determine the tolerability of ATLCAR.CD30.CCR4 cells in subjects with Hodgkin's Lymphoma and identify a recommended dose for further. This is a single-center, open-label phase Ib/II trial that uses a 3+3 design to identify a recommended phase 2 dose (RP2D) of ATLCAR.CD30.CCR4 cells in Hodgkin's Lymphoma. The phase II portion is designed to determine the PFS of ATLCAR.CD30.CCR4 in Hodgkin's Lymphoma. Subjects will be enrolled on 1 of 3 dose levels as determined by a 3+3 design. Up to 25 evaluable subjects may then be enrolled in the phase II portion of the study. Subjects may have cells procured to manufacture the ATLCAR.CD30.CCR4 cells if they meet eligibility for procurement. During the time period necessary to manufacture the ATLCAR.CD30.CCR4 cells, Subjects will be allowed to receive standard-of-care bridging therapy at the discretion of their local oncologist. Prior to cell infusion, subjects will undergo additional eligibility evaluations, and then if eligible, will undergo lymphodepletion followed by cell infusion 2-14 days later. Subjects will then be followed for 15 years as is required for studies involving gene transfer experiments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, you can receive standard-of-care treatments like chemotherapy or radiation during certain parts of the trial, as long as your doctor thinks it's best for you.

What data supports the effectiveness of the treatment ATLCAR.CD30.CCR4 for Hodgkin's Lymphoma?

Research shows that T lymphocytes modified to target the CD30 antigen and express CCR4 have improved ability to reach and attack Hodgkin lymphoma cells, leading to better tumor control in preclinical models. Additionally, CD30-directed CAR-T cells have shown preliminary effectiveness in clinical trials for relapsed or refractory Hodgkin lymphoma, with minimal side effects. ^{1 2 3 4 5}

Is the cell therapy targeting CD30 safe for humans?

The cell therapy targeting CD30, known as CAR T-cell therapy, is generally considered safe for humans with Hodgkin lymphoma, showing minor side effects and low risk of causing tumors. However, some serious side effects like cytokine release syndrome and neurotoxicity have been reported in certain cases. ^{4 5 6 7 8}

What makes the ATLCAR.CD30.CCR4 treatment unique for Hodgkin's Lymphoma?

The ATLCAR.CD30.CCR4 treatment is unique because it uses modified T cells (a type of immune cell) to specifically target the CD30 protein found on Hodgkin lymphoma cells, potentially offering a more precise attack on the cancer with fewer side effects compared to traditional chemotherapy. ^{1 2 4 5 9}

Research Team

Natalie S. Grover

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults over 18 with Classical Hodgkin Lymphoma, who have a Karnofsky score above 60%, indicating they can care for themselves. They must consent to the study and allow their health information to be used. Patients already receiving standard treatments like chemotherapy or radiation may still qualify.

Inclusion Criteria

I can receive standard treatments to manage my condition until the study treatment starts.

I have been diagnosed with Classical Hodgkin Lymphoma.

Unless otherwise noted, subjects must meet all of the following criteria to participate in all phases of the study. As these criteria are unchanging they will be evaluated at the time of initial enrollment and not continuously throughout the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Manufacturing and Bridging Therapy

Subjects may have cells procured to manufacture the ATLCAR.CD30.CCR4 cells and receive standard-of-care bridging therapy during this period

Variable

Lymphodepletion and Cell Infusion

Subjects undergo lymphodepletion followed by infusion of ATLCAR.CD30.CCR4 cells

2-14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• ATLCAR.CD30.CCR4
• Chemotherapy

Trial Overview The trial tests ATLCAR.CD30.CCR4 cells in patients with Hodgkin's Lymphoma. It's an early-phase study determining safe dosage levels and how well these cells work as treatment. Participants will receive cell infusions after a preparatory 'lymphodepletion' process, followed by long-term monitoring.

Participant Groups

Group I: ATLCAR.CD30 Experimental Treatment 2 Interventions

Subjects will be enrolled on 1 of 3 dose levels as determined by a 3+3 design. Up to 25 evaluable subjects may then be enrolled in the phase II portion of the study. Subjects may have cells procured to manufacture the ATLCAR.CD30.CCR4 cells if they meet eligibility for procurement. During the time period necessary to manufacture the ATLCAR.CD30.CCR4 cells, Subjects will be allowed to receive standard-of-care bridging therapy at the discretion of their local oncologist. Prior to cell infusion, subjects will undergo additional eligibility evaluations, and then if eligible, will undergo lymphodepletion followed by cell infusion 2-14 days later. Subjects will then be followed for 15 years as is required for studies involving gene transfer experiments

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

Findings from Research

CD30-directed CAR-T cells show promise as a treatment for relapsed or refractory lymphomas, particularly classical Hodgkin lymphoma, with early clinical trials indicating minimal toxicity and some preliminary efficacy.

Enhancing the persistence and expansion of CAR-T cells is crucial for improving treatment outcomes, with ongoing research focusing on optimizing treatment regimens and combining therapies to boost effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges of driving CD30-directed CAR-T cells to the clinic. Grover, NS., Savoldo, B.[2020]

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]

The study highlights that Hodgkin lymphoma cells produce specific chemokines (TARC/CCL17 and MDC/CCL22) that attract regulatory T cells, creating an immunosuppressive environment that hinders effector CD8(+) T cell activity.

By engineering effector T cells to express the CCR4 receptor, researchers improved their ability to migrate to Hodgkin lymphoma cells, enhancing their tumor-fighting capabilities and leading to better tumor control in mouse models, suggesting a promising strategy for treating patients with Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Di Stasi, A., De Angelis, B., Rooney, CM., et al.[2023]

The study developed a novel CD30-chimeric antigen receptor (CAR) T cell therapy using memory stem T cells (TSCM), which showed improved persistence and antitumor activity against Hodgkin lymphoma in mouse models.

CD30-CAR TSCM-like cells effectively eradicated Hodgkin lymphoma tumors in vivo, demonstrating a survival advantage and enhanced tumor infiltration compared to more differentiated CAR T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma. Alvarez-Fernández, C., Escribà-Garcia, L., Caballero, AC., et al.[2022]

Chimeric antigen receptor (CAR)-transduced T cells targeting CD30 have shown to be safe and effective in treating Hodgkin lymphoma (HL).

The review also highlights the challenges and ongoing trials of using CAR-T cells targeting CD5 and CD7 in T-cell lymphomas (TCL), indicating a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Hodgkin and T-Cell Lymphomas. Muhsen, IN., Hill, LC., Ramos, CA.[2023]

Third-generation anti-CD30 CAR T-cells (CD28BBz) show long-term persistence and strong anti-tumor activity in models of Hodgkin lymphoma and anaplastic large cell lymphoma, outperforming second-generation CAR T-cells (CD28z).

These CAR T-cells are well tolerated with minimal side effects, indicating they are a safe and effective treatment option for patients with Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The third-generation anti-CD30 CAR T-cells specifically homing to the tumor and mediating powerful antitumor activity. Zhang, S., Gu, C., Huang, L., 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]

In a phase I study involving 9 patients with relapsed/refractory Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL), CD30-targeted CAR T-cell therapy was found to be safe, with no observed toxicities related to the treatment.

The therapy resulted in significant clinical responses, including complete responses in 2 patients and stable disease in several others, suggesting that CD30.CAR-Ts could be an effective treatment option for these lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. Ramos, CA., Ballard, B., Zhang, H., et al.[2022]

Hodgkin lymphoma (HL) has a high cure rate of nearly 70% with initial chemotherapy, but about 50% of patients relapse after autologous hematopoietic cell transplantation (auto-HCT), indicating a need for better treatment options for this subgroup.

Emerging treatments like chimeric antigen receptor T-cell therapy targeting CD30 show promising safety and efficacy in early clinical trials for patients with relapsed or refractory HL, offering hope for potentially curative options after auto-HCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation: A current management perspective. Iqbal, M., Kharfan-Dabaja, MA.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Challenges of driving CD30-directed CAR-T cells to the clinic. [2020]

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

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

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

T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. [2023]

4. Australia pubmed.ncbi.nlm.nih.gov

Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma. [2022]

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

Chimeric Antigen Receptor T Cells in Hodgkin and T-Cell Lymphomas. [2023]

6. England pubmed.ncbi.nlm.nih.gov

The third-generation anti-CD30 CAR T-cells specifically homing to the tumor and mediating powerful antitumor activity. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. [2022]

9. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation: A current management perspective. [2021]