CAR T-Cell Therapy for Lymphoma

Overseen By Kelly Hoye

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Corticosteroids, CYP1A2 inhibitors

Disqualifiers: Pregnancy, Active infection, HIV, others

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

Compensation: Varies

Number of Visits: 4

Duration: Single infusion

20 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 take certain medications that are contraindicated (not allowed) during the trial, and these should be stopped at least two weeks before lymphodepletion. It's best to discuss your current medications with the study team to ensure they are not prohibited.

What data supports the effectiveness of this treatment for lymphoma?

Research shows that CAR T-cell therapy, which involves modifying T cells to target specific proteins on cancer cells, has been effective in treating B-cell lymphomas. Studies have demonstrated that T cells targeting the kappa light chain can kill cancerous B cells while sparing some normal B cells, suggesting potential effectiveness in treating lymphoma. ^{1 2 3 4 5}

Is CAR T-Cell Therapy for Lymphoma safe for humans?

CAR T-Cell Therapy has shown safety in treating B-cell lymphomas, but it can have side effects, including cardiovascular issues and increased infection risk due to compromised B-lymphocyte recovery. ^{1 3 5 6 7}

How is the CAR.k.28 treatment different from other treatments for lymphoma?

The CAR.k.28 treatment is unique because it targets the kappa light chain on B-cells, which allows it to kill cancerous B-cells while sparing normal B-cells that express the lambda light chain, potentially reducing the risk of impairing the immune system compared to other CAR T-cell therapies that target CD19. ^{1 2 3 4 8}

What is the purpose of this trial?

This study will combine both T cells and antibodies in order to create a more effective treatment. The treatment tested in this study uses modified T-cells called Autologous T Lymphocyte Chimeric Antigen Receptor (ATLCAR) cells targeted against the kappa light chain antibody on cancer cells. For this study, the anti-kappa light chain antibody has been changed so instead of floating free in the blood, a part of it is now joined to the T cells. Only the part of the antibody that sticks to the lymphoma cells is attached to the T cells. When an antibody is joined to a T cell in this way, it is called a chimeric receptor. The kappa light chain chimeric (combination) receptor-activated T cells are called ATLCAR.κ.28 cells. These cells may be able to destroy lymphoma cancer cells. They do not, however, last very long in the body so their chances of fighting the cancer are unknown. Previous studies have shown that a new gene can be put into T cells to increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying your genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells in this study makes an antibody called an anti-kappa light chain. This anti-kappa light chain antibody usually floats around in the blood. The antibody can detect and stick to cancer cells called lymphoma cells because they have a substance on the outside of the cells called kappa light chains. The purpose of this study is to determine whether receiving the ATLCAR.κ.28 cells is safe and tolerable and learn more about the side effects and how effective these cells are in fighting lymphoma. Initially, the study doctors will test different doses of the ATLCAR.κ.28, to see which dose is safer for use in lymphoma patients. Once a safe dose is identified, the study team will administer this dose to more patients, to learn about how these cells affect lymphoma cancer cells and identify other side effects they might have on the body. This is the first time ATLCAR.κ.28 cells are given to patients with lymphoma. The Food and Drug Administration (FDA), has not approved giving ATLCAR.κ.28 as treatment for lymphoma. This is the first step in determining whether giving ATLCAR.κ.28 to others with lymphoma in the future will help them.

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 chronic lymphocytic leukemia/small lymphocytic lymphoma that have relapsed or are not responding to treatment. Participants must have adequate organ function, no uncontrolled infections, and women of childbearing potential must use birth control. Those with active hepatitis, HIV, certain other cancers, or intolerance to specific drugs cannot join.

Inclusion Criteria

My lymphoma is between DLBCL and Hodgkin.

Written informed consent and HIPAA authorization for release of personal health information

I have been diagnosed with a type of blood cancer that has come back or didn’t respond to treatment.

Exclusion Criteria

I have been diagnosed with lymphoma, Waldenstrom's macroglobulinemia, or multiple myeloma.

A history of intolerance to bendamustine or fludarabine

I have been tested for hepatitis B and need to check my viral load.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Procurement

Peripheral blood is collected for production of CAR.κ.28 cells, with possible leukapheresis if needed.

1-2 months

Up to 3 collections

Lymphodepletion

Subjects receive a pre-conditioning cytoreductive regimen of bendamustine and fludarabine or cyclophosphamide and fludarabine.

3 days

Treatment

Administration of CAR.κ.28 cells via intravenous injection after lymphodepletion.

Single infusion

1 visit (in-person)

Follow-up

Participants are monitored for safety, efficacy, and persistence of CAR.κ.28 cells.

15 years

Treatment Details

Interventions

• Bendamustine
• CAR.k.28
• Cyclophosphamide
• Fludarabine

Trial Overview The study tests a new therapy using T cells engineered to carry a chimeric antigen receptor (CAR) targeting the kappa light chain on cancer cells. It aims to determine the safety and effectiveness of these modified T cells (ATLCAR.κ.28) in treating lymphoma by starting with various doses before settling on one for further evaluation.

Participant Groups

Group I: CAR.k.28/CAR.k.4-1BB Experimental Treatment 4 Interventions

Up to 12 patients will receive a single infusion of CAR.k.28. The starting dose will be 2.5x10\^5 cells/kg of each product. Up to 3 dose levels of CAR.k.28 cells will be tested with at least 3 patients enrolled at each dose cohort before dose escalation is considered based on the incidence of dose limiting toxicity (DLT). An expansion cohort will enroll up to 8 patients at the recommended phase 2 dose. Prior to receiving the infusions, patients will undergo lymphodepletion with fludarabine and bendamustine. Patients with a known history of intolerance to bendamustine may be considered for lymphodepletion with fludarabine and cyclophosphamide.

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+

Findings from Research

Genetically modified T cells targeting the kappa light chain can effectively kill Igkappa(+) tumor cells and B-CLL cells, potentially offering a treatment for B-cell lymphomas while preserving normal B cells that express lambda light chains.

Incorporating the CD28 endodomain in the CAR enhances the growth and effectiveness of these modified T cells, allowing them to proliferate and maintain their ability to target tumors even in the presence of free immunoglobulins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Vera, J., Savoldo, B., Vigouroux, S., 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]

CAR.λ T cells effectively target and kill Igλ+ lymphoma cells and chronic lymphocytic leukemia (CLL) cells, showing similar antitumor activity to the established CAR.CD19 T cells in both laboratory and animal models.

Importantly, CAR.λ and CAR.κ T cells selectively deplete only the corresponding light chain-expressing normal B cells, preserving the other type, which suggests a safer approach with minimal impact on the immune system's ability to produce antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells. Ranganathan, R., Shou, P., Ahn, S., 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]

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]

Chimeric antigen receptor T cell therapy, while effective for treating B cell lymphomas, can lead to significant cardiovascular toxicities, including hypotension and heart failure, primarily due to cytokine release syndrome.

Current clinical practices for managing these toxicities are not standardized, highlighting the need for further research into the mechanisms of cardiac dysfunction and effective treatment strategies to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Cardiovascular Complications of Chimeric Antigen Receptor T Cell Therapy. Jamal, FA., Khaled, SK.[2020]

CAR T cell therapy has shown high response and remission rates in patients with aggressive B-cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma, particularly in those who have undergone extensive prior treatments.

The article discusses not only the indications for CAR T cell therapy approval but also its clinical implementation and how to manage potential side effects, highlighting its practical application in treating difficult cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CAR-T cell therapy - personalized cellular immunotherapy in 2022]. Niebling, J., Bethge, W., Lengerke, C.[2022]

CAR-T cell therapy combined with anti-PD-1 immunotherapy shows promising efficacy in treating lymphoma, with an overall response rate of 65% based on an analysis of 57 patients from 5 clinical trials.

The most common adverse effect observed was fever, with a pooled incidence of 59%, indicating that while the therapy is effective, it does come with notable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients. Zhou, Y., Mu, W., Wang, C., et al.[2023]

References

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

T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant 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

CAR T cells Targeting Human Immunoglobulin Light Chains Eradicate Mature B-cell Malignancies While Sparing a Subset of Normal B Cells. [2022]

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

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. [2017]

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

CARs and cancers: questions and answers. [2021]

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

The Cardiovascular Complications of Chimeric Antigen Receptor T Cell Therapy. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

[CAR-T cell therapy - personalized cellular immunotherapy in 2022]. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients. [2023]