Azer-cel, a New CAR T-Cell Therapy for DLBCL

Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin lymphoma (NHL). Innovative treatments are being studied to provide new options for patients with relapsed or refractory DLBCL, especially after multiple lines of therapy. This article will guide you through a current clinical trial NCT03666000 that uses Azer-cel the first allogeneic CAR T-cell therapy, alongside other medications.

How Azer-cel, an Allogeneic CAR T-cell Therapy Works

Allogeneic CAR T-cell therapy offers an innovative approach to treating certain types of cancer by using genetically modified T-cells from a healthy donor to target cancer cells. 

Some of the advantages of this type of therapy are: 

• It is especially beneficial for patients who cannot undergo autologous (self-derived) CAR T-cell therapy
• Offers faster availability and reduces manufacturing delays
• The donor cells are generally healthier, they may be more effective at targeting and killing cancer cells. 

What is the Clinical Trial’s Purpose?

Allogeneic CAR T-cell therapy also comes with risks, including a higher chance of graft-versus-host disease (GVHD), where the donor T cells attack healthy tissues in the patient’s body. Other risks include immune rejection and infection, as patients undergo immune suppression to allow the donor cells to function effectively. Despite these risks, this therapy continues to show promise in trials, offering hope for patients with hard-to-treat cancers.

The primary goal of this clinical trial, NCT03666000, is to evaluate the safety and effectiveness of Azer-cel, a CAR T-cell therapy, for patients with relapsed or refractory B-cell malignancies, including DLBCL. This therapy is specifically tested in patients who have undergone at least two prior treatments, including chemotherapy and immunotherapy (such as anti-CD20 monoclonal antibody therapy) or CAR T-cell therapy.

Who Can Participate in This Clinical Trial?

 This trial focuses on patients with the following conditions:

1. Diffuse large B-cell lymphoma (DLBCL), including Richter's transformation.

2. Follicular lymphoma (FL), including Grade 3 or transformed follicular lymphoma.

3. High-grade B-cell lymphoma.

4. Primary mediastinal B-cell lymphoma.

For the Phase 1b dose expansion, eligible patients include those with:

• DLBCL not otherwise specified (NOS).

• DLBCL transformed from other lymphomas like follicular lymphoma, marginal zone lymphoma, and Waldenström’s macroglobulinemia.

To qualify, patients must have received at least two prior lines of treatment (except for Richter's transformation, which requires only one) and must show measurable disease.

So far, 10 patients have been treated in this Phase 1b trial for DLBCL. The trial is divided into two cohorts:

These findings are encouraging, especially for patients who have failed multiple prior treatments, including CAR T therapies.

What Medications Are Used in the Trial?

1. Azer-cel (Azercabtagene Zapreleucel) is an allogeneic CAR T-cell therapy that modifies a patient's own immune cells to recognize and attack cancer cells. It targets CD19, a protein commonly found in B-cell lymphomas, making it particularly effective for relapsed or refractory DLBCL.

2. Fludarabine is a type of chemotherapy that disrupts the DNA synthesis of cancer cells, leading to their death. It is part of the conditioning regimen before Azer-cel infusion, it prepares the body to accept the CAR T-cells.

3. Cyclophosphamide is an alkylating agent that causes breaks in the DNA of cancer cells, leading to their destruction. Like fludarabine, it is part of the pre-treatment regimen to help prepare the patient for CAR T-cell therapy.

4. Interleukin-2 (IL-2) is an immunotherapy that boosts the immune system by stimulating the production of immune cells like T-cells and natural killer (NK) cells. In this trial, it is used in Cohort B to enhance the activity of the Azer-cel therapy.

5. Bendamustine is a chemotherapy drug that combines the properties of both an alkylating agent and an antimetabolite, it disrupts cancer cell function. Is included in Cohort B to increase the effectiveness of the CAR T-cell therapy.

Looking Ahead: What This Means for Patients

This clinical trial represents a significant step forward for patients with relapsed or refractory DLBCL who have exhausted other treatment options. Combining CAR T-cell therapy with lymphodepletion (fludarabine and cyclophosphamide) and immunotherapy (IL-2) could offer more durable remissions. While the trial is ongoing, the early results show that this combination is not only effective but also tolerable, with manageable side effects.

For patients with DLBCL and related conditions who have relapsed after multiple lines of therapy, participating in clinical trials trials might offer a path toward remission and a longer life.

Final Thoughts

This clinical trial's success, especially with Cohort B (Azer-cel with lymphodepletion, fludarabine and cyclophosphamide), is planned to be part of a potential Phase 2/3 FDA registration package, which means it could one day become a standard treatment option for DLBCL patients. If you or a loved one are considering clinical trials, this might be an opportunity to explore with your healthcare provider.

If you want to learn more about treatment options for DLBCL, you can watch one of our recent webinars, led by distinguished expert Dr. Tycel Phillips from City of Hope. In this webinar, he covers the latest advancements, treatment strategies, and personalized care approaches for managing DLBCL. 

WATCH WEBINAR

Sources: 

• Dose-escalation, Dose-expansion Study of Safety of Azer-cel (PBCAR0191) in Patients With r/​r NHL and r/​r B-cell ALL

• Three Complete Responses in Azer-Cel Allogeneic CD19 CAR T Phase 1b Trial in Blood Cancer (Diffuse Large B-Cell Lymphoma)