CAR-T Cell Therapy for Lymphoma

Overseen By Caroline Babinec

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must be taking: Brentuximab vedotin

Must not be taking: Systemic corticosteroids, CYP1A2 inhibitors

Disqualifiers: Pregnancy, HIV, HBV, others

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

Compensation: Varies

Number of Visits: 7

Duration: 1-2 weeks

59 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new lymphoma treatment using a combination of special proteins and immune cells. The treatment modifies T cells (a type of immune cell) to better target and kill cancer cells. Researchers are testing two versions: ATLCAR.CD30, which targets cancer cells more effectively, and ATLCAR.CD30.CCR4, which helps guide these cells to the cancer. Individuals with lymphoma that has returned or didn't respond to at least two other treatments might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot use strong inhibitors of CYP1A2 (like fluvoxamine or ciprofloxacin) during certain parts of the study. Also, you cannot be on systemic corticosteroids at doses of 10mg or more of prednisone daily.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that anti-CD30 CAR-T cell therapy is generally safe for people with Hodgkin lymphoma. Studies indicate that patients usually tolerate this treatment well, with some experiencing mild side effects like tiredness or fever, common in many cancer treatments.

For the ATLCAR.CD30.CCR4 cells, currently undergoing initial testing, researchers are still assessing safety. In this early testing stage, they closely monitor participant responses. This type of study helps determine the right dose and identify potential side effects early.

Overall, while side effects like skin rashes or lower blood cell counts might occur, researchers are carefully studying these treatments to understand and manage any risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike most standard treatments for lymphoma, which typically involve chemotherapy and radiation, ATLCAR.CD30 and ATLCAR.CD30.CCR4 are innovative CAR-T cell therapies. These treatments work by genetically modifying a patient's own T-cells to better recognize and attack cancer cells, specifically targeting the CD30 protein often found on lymphoma cells. This targeted approach not only has the potential to improve effectiveness but also reduce collateral damage to healthy cells, which is a common issue with traditional treatments. Researchers are excited about these therapies because they represent a personalized and potentially more precise attack on cancer, offering hope for better outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for lymphoma?

Research has shown that CD30-directed CAR-T cells offer promise in treating lymphoma, a type of cancer. Many patients have responded well, with some experiencing long-lasting remissions. These CAR-T cells are designed to find and kill cancer cells by recognizing a protein called CD30 on their surface. However, the positive effects have not lasted for all patients, and the treatment has not always completely cured the cancer.

In this trial, participants will receive either ATLCAR.CD30.CCR4 cells alone or a combination of ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells. The ATLCAR.CD30.CCR4 cells are designed to locate cancer cells more easily by using a protein called CCR4, which guides them like a GPS. Early results suggest this might help the treatment target and destroy cancer cells more effectively. Combining these approaches could lead to better outcomes for people with lymphoma. ^{1 5 6 7 8}

Who Is on the Research Team?

Natalie S. Grover

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with certain types of lymphoma, like Mycosis fungoides or Sezary syndrome, that have not improved after at least two treatments. Participants must have CD30+ disease and adequate organ function. They cannot be on strong CYP1A2 inhibitors, have uncontrolled infections, or be pregnant. Those with HIV, HTLV, HCV or active hepatitis B are excluded.

Inclusion Criteria

Subjects must have one of the following diagnoses by WHO criteria: Classic Hodgkin Lymphoma, Mycosis fungoides, Sezary syndrome, Primary cutaneous CD30 positive T cell lymphoproliferative disorder including lymphomatoid papulosis or primary cutaneous anaplastic large cell lymphoma, B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin Lymphoma (Grey Zone Lymphoma), Diagnosis of recurrent lymphoma in subjects who have failed ≥2 prior treatment regimens (including brentuximab vedotin), Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for this study, CD30+ disease (result can be pending at the time of cell procurement, but must be confirmed prior to treatment with ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells)

I am willing to have a biopsy after receiving cell infusion.

I have signed the consent form for the CAR T-cell therapy trial before starting lymphodepletion.

Exclusion Criteria

I have another cancer that is growing and needs treatment.

I do not have an active HIV, HTLV, or HCV infection.

I do not have any ongoing serious infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Procurement

Up to 300 mL total of peripheral blood will be obtained for cell procurement, with leukapheresis performed if necessary.

1-2 weeks

Up to 3 visits (in-person)

Lymphodepletion

Subjects will receive lymphodepletion with bendamustine and fludarabine for 3 days prior to CAR-T cell infusion.

1 week

3 visits (in-person)

Treatment

Administration of ATLCAR.CD30.CCR4 with or without ATLCAR.CD30 cells, with potential for a second infusion.

1-2 weeks

1-2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including long-term follow-up for replication competent retrovirus (RCR) evaluation.

15 years

What Are the Treatments Tested in This Trial?

Interventions

• ATLCAR.CD30
• ATLCAR.CD30.CCR4
• Bendamustine
• Fludarabine

Trial Overview The study tests new cancer treatments using T cells genetically modified to target CD30+ lymphoma cells. One group receives ATLCAR.CD30.CCR4 cells designed to navigate towards tumors; another gets these plus additional ATLCAR.CD30 cells. The goal is to find the safest dose for these therapies.

How Is the Trial Designed?

Group I: ATLCAR.CD30.CCR4 & ATLCAR.CD30 Experimental Treatment 4 Interventions

A 3+3 design in adult subjects. Subjects in the first dose level will receive ATLCAR.CD30.CCR4 cells alone, once safety has been established, the initial dose of ATLCAR.CD30.CCR4 will be combined with a fixed dose of ATLCAR.CD30 cells in the next dose level. Every time the dose of ATLCAR.CD30.CCR4 is escalated, subjects in that dose level will receive ATLCAR.CD30.CCR4 alone prior to subsequent dose level enrolling subjects to receive a combination of fixed dose ATLCAR.CD30 and the selected dose level of ATLCAR.CD30.CCR4. The six dose levels will consist of: dose level 1 = 2 × 10\^7 ATLCAR.CD30.CCR4 cells/m2; dose level 2 = 1 × 10\^8 ATLCAR.CD30 cells/m2 and 2 × 10\^7 ATLCAR.CD30.CCR4 cells/m2; dose level 3 = 5 × 10\^7/m2 ATLCAR.CD30.CCR4 cells/m2; dose level 4 = 1 × 10\^8 ATLCAR.CD30 cells/m2 and 5 × 10\^7 ATLCAR.CD30.CCR4 cells/m2; dose level 5 = 1 × 10\^8/m2 ATLCAR.CD30.CCR4 cells/m2; dose level 6 = 1 × 108 ATLCAR.CD30 cells/m2 and 1 × 108 ATLCAR.CD30.CCR4 cells/m2.

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

University Cancer Research Fund at Lineberger Comprehensive Cancer Center

Collaborator

Trials

5

Recruited

150+

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Published Research Related to This Trial

T cells from a patient with cutaneous T cell lymphoma can be engineered to specifically target and kill their own tumor cells by using a recombinant anti-CD30 receptor, showing a high efficiency in lysis even at low ratios of T cells to tumor cells (1:20).

This approach successfully enhances the immune response by overcoming T cell tolerance to the tumor, leading to increased secretion of IFN-gamma and targeted destruction of CD30+ lymphoma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells engrafted with a recombinant anti-CD30 receptor target autologous CD30(+) cutaneous lymphoma cells. Hombach, A., Muche, JM., Gerken, M., et al.[2020]

CD30 is a promising target for cancer treatment because it is highly expressed in tumors but has low levels in healthy tissues, making therapies that target it potentially safer and more effective.

Various therapeutic strategies have been developed against CD30, including monoclonal antibodies and CAR-T cell therapies, which show promise in treating lymphoid neoplasms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD30 as a therapeutic target in adult haematological malignancies: Where are we now? Veyri, M., Spano, JP., Le Bras, F., et al.[2023]

CAR T cell therapy targeting CD19 has shown high efficacy in treating relapsed or refractory aggressive B cell non-Hodgkin lymphoma, leading to durable remissions in many patients, as demonstrated in multicenter trials.

The most common side effects of this therapy include cytokine release syndrome and neurotoxicity, highlighting the need for ongoing research to improve safety and explore its use in earlier treatment stages and other types of B cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-Engineered T Cell Therapy in Lymphoma. Strati, P., Neelapu, SS.[2020]

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]

The study demonstrates that CD30-targeted CAR-T cell therapy is effective in treating recurrent and malignant CD30-positive peripheral T-cell lymphomas (PTCL), showing significant tumor suppression in both laboratory and mouse model experiments.

The engineered 9C11-2 CAR T cells exhibited strong cytotoxic effects against CD30-positive cancer cells, indicating their potential as a promising therapeutic option for patients with this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new immunotherapy strategy targeted CD30 in peripheral T-cell lymphomas: CAR-modified T-cell therapy based on CD30 mAb. Wu, Y., Chen, D., Lu, Y., et al.[2022]

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]

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]

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]

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 combination of autologous stem-cell transplantation (ASCT) and CAR30 T-cell therapy was found to be safe and effective in treating relapsed/refractory CD30+ lymphoma, with 83.3% of patients achieving a complete response after treatment.

In a pilot study involving 6 patients, all of whom had previously poor prognoses, the treatment resulted in successful engraftment and maintained responses over a median follow-up of 20.4 months, indicating promising long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous stem cell transplantation in tandem with Anti-CD30 CAR T-cell infusion in relapsed/refractory CD30+ lymphoma. Zhang, P., Yang, X., Cao, Y., et al.[2022]

CAR T-cells are engineered T-cells that target the CD19 antigen, showing promising initial results in treating various B-cell malignancies, including acute lymphocytic leukaemia and chronic lymphocytic leukaemia.

While the treatment shows potential, there are significant differences in patient responses and notable side effects that require careful management, highlighting the need for personalized approaches in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. Heijink, DM., Kater, AP., Hazenberg, MD., et al.[2017]

CAR T cell therapy has become an important treatment for certain blood cancers, with three types of anti-CD19 CAR-T cells already approved for use in the Czech Republic, and more trials underway for targeting other cancer-specific antigens.

While the management of CAR-T cell therapy has improved, including updated guidelines for early toxicity, long-term follow-up is essential due to potential late toxicities, highlighting the need for ongoing research to enhance efficacy and reduce side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical aspects of CAR-T cell therapy. Jana, M., Tomáš, J., Michal, K., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10394544/

Patient-reported outcomes in CD30-directed CAR-T cells ... Chimeric antigen receptor (CAR)-T cells targeting CD30 have demonstrated high response rates with durable remissions observed in a subset of ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11731380/

Safety and efficacy of anti-CD30 CAR-T cell therapy in ... Current evidence suggests that anti-CD30 CAR-T cell therapy is effective and safe in treating R/R cHL and is worth considering as a viable therapeutic option.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02917083

Study Details | NCT02917083 | CD30 CAR T Cells, ... This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with ...

4. ashpublications.org ashpublications.org/bloodadvances/article/8/3/802/498655/Transient-responses-and-significant-toxicities-of

Transient responses and significant toxicities of anti-CD30 ... Anti-CD30 CAR T cells had low efficacy in patients with CD30-expressing lymphoma. Rashes and prolonged cytopenias were frequent and severe in some cases ...

5. nature.com nature.com/articles/s41598-022-14523-0

The third-generation anti-CD30 CAR T-cells specifically ... CAR T-cell therapy is well tolerated and effective in patients with Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL).

6. aacrjournals.org aacrjournals.org/clincancerres/article/23/5/1156/123036/Autologous-T-Cells-Expressing-CD30-Chimeric

Autologous T Cells Expressing CD30 Chimeric Antigen ... We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT07048353?limit=100&rank=37

CD30 CAR-T in the Treatment of CD30 Positive Lymphoma The goal of this clinical trial is to explore the efficacy and safety of CD30 CAR-T on CD30 positive relapsed/refractory lymphoma. The main questions it aims to ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2352302624000644

Anti-CD30 CAR T cells as consolidation after autologous ... Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to ...