CAR T-Cell Therapy Treatment for Diffuse Large B Cell NHL-An Update

Two year outcomes reported in Lancet for patients with recurrent B-cell NHL treated with Yescarta CAR - T cells.

by Dr. C.H. Weaver M.D. updated 1/2019

The US Food and Drug Administration (FDA) approved the second T-cell therapy that uses chimeric antigen receptor (CAR) technology in 2018.(1)

Yescarta (Axicabtagene ciloleucel) received FDA approval for the treatment of patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.(2)

This approval occured on the heels of the FDA’s approval of Kymriah (tisagenlecleucel-T), the first therapy CAR technology therapy to be approved.

CAR therapies utilize T-cells (CART T), a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes, these T cells are re-programmed to identify a patient’s cancer cells.

Once the T cells have been programmed to identify a patient’s cancer cells, they are replicated in the laboratory, and infused back into the patient. These re-programmed T cells circulate throughout the body, identifying the cancer cells and mounting an immune attack against them. Simultaneously, the T cells are replicating within the body, so that more of the immune cells can identify and attack the cancer cells.

Long-Term Outcomes of Yescara

The ZUMA-1 clinical trial enrolled 119 adults with relapsed or refractory large B-cell lymphoma to receive treatment with a chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of Yescarta.

In the ZUMA-1 clinical trial, Yescarta showed durable responses and no new safety concerns in patients with relapsed or refractory large B-cell lymphoma according to 2-year follow-up data published in Lancet Oncology.

Overall 83% of treated patients responded to treatment and 58% had a complete response. Thirty-nine patients (39%) had an investigator-assessed ongoing response, with a median duration of response of 11.1 months. The median overall survival was not yet reached.

Fifty patients died from progressive lymphoma while on study, with 6 deaths occurring during the first year follow-up analysis. Four patient deaths were related to adverse events, 2 of which were related to treatment with Yescarta.

According to the study authors"the 2-year follow-up data from ZUMA-1 suggest that Yescarta can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma."

Additional side effects were reported at the 2-year follow-up for 4 patients and included mental status changes, development of a myelodysplastic syndrome, a lung infection, and 2 episodes of sepsis. The study authors believe that none of these events were treatment related.

While the initial FDA approval is for "transplant inelgiible patients" there is of course great hope that CAR T cell therapy will also improve the outcomes compared with stem cell transplant used earlier in the disease course. It is of interest that the treatment related mortality of ~ 4% and the 2 year disease free survival are similar to that obtained with a standard stem cell transplant. Comparative clinical trials may be necessary to determine how the side effects compare to a standard stem cell transplant and whether the additional cost for CAR-T cell therapy is warranted.

Fred Hutchinson Cancer Research Center statement regarding FDA approval of immunotherapy drug Yescarta

Dr. David Maloney, medical director of cellular immunotherapy offered the following statement:

“While the Food and Drug Administration’s first approval of a CAR T-cell therapy impacted a relatively small number of pediatric and young adult patients, today’s decision opens the door for a cellular immunotherapy to treat adults with aggressive lymphoma. There will likely be thousands of lives saved in the next few years because of it.

“The FDA’s ruling validates the revolution under way in the field of cellular immunotherapy, which enables us to engineer patients’ own immune systems to eliminate cancer cells. We at Fred Hutchinson Cancer Research Center believes that by 2025 there will be many approved T- cell therapies for a variety of cancers.

“The current CAR T-cell therapies need to become more effective, more affordable and safer. We need to understand why they do not work for certain people, why they only work in select types of cancer and why they can cause severe, occasionally fatal, side effects.

“To answer these questions, we at Fred Hutch and Seattle Cancer Care Alliance have ongoing clinical trials and will continue to launch new ones. We have shared treatment algorithms and biomarkers that could help prevent serious harm that can be caused by treatment side effects such as cytokine release syndrome and neurotoxicity, and we are working to perfect these methods of averting such dire side effects. We must step up our already intense study of how the immune system interacts with cancer.

“We are poised to make great advances if we can continue to build stronger partnerships with the private sector and see government support grow at a steady pace. Increased collaboration and funding will allow us to make further investments in fundamental research and development so that these experimental therapies become more widely available and affordable.”

Scientists at Fred Hutch are testing new experimental T-cell therapies for breast cancer, leukemia, lymphoma, lung cancer, Merkel cell carcinoma, mesothelioma and multiple myelomas.


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