CAR T-Cell Therapy Transforms Leukemia and Lymphoma Treatment, But Toxicity Concerns Remain

Following the approvals of tisagenlecleucel (tisa-cel; Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta), several research efforts have been dedicated to the development and exploration of CAR T-cell therapies in the realm of leukemias and lymphomas, according to Olalekan O. Oluwole, MBBS, MD, who added that although this modality has moved the needle forward, this approach is not without toxicity.

“CAR T-cell therapy has transformed the treatment paradigm for patients with relapsed/refractory leukemia and lymphoma. However, it’s critical to remember that despite the great results we have seen thus far [with this approach], some toxicities are associated with these products,” said Oluwole. “Looking forward, we hope to lessen these toxicities and use cellular therapy in combination with other agents. Ultimately, we hope that, with time, the success that has been achieved in hematologic malignancies will roll over to solid tumors.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Oluwole, who is an assistant professor of medicine, hematology, and oncology at Vanderbilt-Ingram Cancer Center, highlighted the evolution of CAR T-cell therapy in leukemia and lymphoma, targets under investigation, and next steps for exploration.

OncLive®: Could you expand on research that led to the rise of CAR T-cell therapy in leukemia and lymphoma?

Oluwole: The ZUMA-1 trial led to the approval of the first CAR T-cell product in diffuse large B-cell lymphoma (DLBCL): [axi-cel]. This product has been the poster child for what [the regulatory] process looks like [for this modality] in lymphomas.

In the leukemia space, tisagenlecleucel was the first to be approved for acute lymphoblastic leukemia. Additional products [have since emerged] for other types of leukemia, lymphoma, and multiple myeloma.

Could you further expand on the ZUMA-1 trial and the significance of this research?

ZUMA-1 was a phase 1/2 clinical trial that evaluated the cellular product axi-cel in patients with DLBCL. 

In the [manufacturing] process [for the product], T cells are collected from the patient, they are sent to a central laboratory where they are manipulated in a way that would express a specific antigen receptor that is able to recognize CD19. The T cells are then re-infused back into the patient, where they go after anything that harbors CD19. During this process, they wipe out the lymphoma. A brief course of lymphodepleting chemotherapy is given to patients prior to CAR T infusion and the purpose of is to facilitate rapid proliferation of the infused CAR T cells.

We have seen encouraging long-term reports. Four to 5 years [after] treatment, these patients have not needed any other therapy. About 82% of patients responded [to this modality] and 54% achieved a complete response (CR). This is interesting, because prior to this research, we had salvage therapy and autologous stem cell transplant, which many were not able to get to because they often get sick while receiving chemotherapy.

Historically, if you looked at patients with refractory lymphoma, within 1 year, many of them were in hospice or had died. Now, with CAR T-cell therapy, 54% of patients are achieving a CR and many have maintained durable responses for 4 or 5 years. As such, cellular therapy has changed the treatment paradigm. 

What are some of the targets that are currently under exploration?

When it comes to cellular therapy, we try to target something that is on the leukemia or lymphoma cell. The ones that we are targeting right now also exist on normal cells, but not believed to be on stem cells. As such, even if the CAR T-cell therapy wipes out the normal cells, over time, these cells can repopulate.

CD19 is one target but several other targets [are being examined]. Some FDA-approved or soon-to-be-approved products are targeting BCMA, which is a protein found on multiple myeloma cells and some B cell precursors. Others [products that are] under investigation are targeting CD20 in some lymphomas and leukemias, and CD22 in leukemias.

[Other products are being designed to] target more than one antigen simultaneously. If you only target 1 antigen, it is possible that the leukemia or lymphoma can escape by no longer expressing that target. However, if you target 2 antigens, you can increase the likelihood that the leukemia will not relapse. This method is still early in development.

What are some of the challenges with this modality?

CAR T cells are made from mature human T cells that have been engineered and redirected to target a tumor antigen. The method of engaging the antigen for destruction includes making a lot of cytokines that cause specific side effects including cytokine release syndrome (CRS). This can start as early as 1-4 days after infusion, can last up to 9 days, and consists of fever, low blood pressure and other symptoms. The field has learned how to adequately manage this adverse effect (AE) with agents such as tocilizumab (Actemra) and steroids. e are currently evaluating other ways to lessen the inflammation during treatment with CAR T-cell therapy. Being able to do this will improve make it easier for our patients to tolerate this therapy

Other toxicities, such as neurological toxicity, have also been experienced; this occurs more often in patients who receive lymphoid-targeted products, although it has been described with almost all products. We are still learning more about what causes this toxicity, but it arises in the inflammatory process.

Some patients also experience delayed cytopenias which is sometimes related to the degree of intensity of the lymphodepleting regimen that they were given . Some protocols allow for the use of specific growth factors like G-CSF to minimize the impact of neutropenia.

Normal B cells are also reduced [with this approach], which could lead to B-cell aplasia. However, this is only temporary. Over time, normal B cells will repopulate.

What does the future of CAR T-cell therapy look like?

If anyone is going to hazard a guess as to what the future will look like, off-the-shelf products seem to be the way to go because we can avoid apheresis and the waiting period for the manufacturing of autologous CAR T cells. Even though this period can be as short as17 days, this is a long time for patients with relapsed/refractory disease. To transition to off the shelf products does have some nuances that need to be addressed. None of these products have obtained FDA approval yet, but several ongoing clinical trials are investigating [these approaches].