CAR T-Cell Therapy Treatment for Lymphoma - An Update
by Dr. C.H. Weaver M.D. updated 2/2020
The US Food and Drug Administration (FDA) has approved two chimeric antigen receptor (CAR) technologies for the treatment of malignant lymphoma. Yescarta (Axicabtagene ciloleucel) and Kymriah (tisagenlecleucel-T) are the first CAR therapies to be approved. The results of early-phase clinical studies of “second-generation” CAR T cellular immunotherapy products may overcome resistance, reduce side effects and simplify treatment. Both allogenic umbilical cord blood derived CAR T cells and FT596 appear very promising.
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 Yescarta
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 and uptdated at ASH 2019. (2,5)
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.
With a minimum follow-up of three years after a single infusion of Yescarta (median follow-up of 39.1 months), 47% of patients with refractory large B-cell lymphoma in the ZUMA-1 clinical survive, and the median overall survival was 25.8 months.
KTE - C19
Kite Pharma reported on 51 patients with advanced diffuse large B-cell lymphoma (DLBCL) who were treated with Kite’s KTE-C19. Initially, 76% of the patients responded to treatment, 47% of patients went into complete remission. By comparison, similar DLBCL patients treated again with chemotherapy in previous studies only achieve an 8%-10% complete response rate. Two lymphoma patients in the study died due to treatment with KTE-C19, the company said. Serious neurological toxicity was reported in 34% of patients.Another trial evaluating the effectiveness of CAR T cell therapy included 22 patients with different types of advanced B-cell lymphomas that had progressed following prior therapies. All patients received chemotherapy prior to a single infusion of the CAR T cells.
- Of 19 patients who had different subtypes of diffuse large B-cell lymphoma (DLBCL), 8 achieved a complete disappearance of their cancer; 5 achieved a partial disappearance of their cancer; 2 achieved disease stabilization; and 4 experienced a progression of their disease.
- Of the 2 patients with follicular lymphoma, and the single patient with mantle cell lymphoma, all achieved a complete disappearance of their cancer.
- Two patients with refractory chronic lymphocytic leukemia are reported to be in complete remission for 8 years as of May 2019.
KTE-X19 for Mantle Cell Lymphoma
Ninety-three percent of patients with relapsed/refractory MCL responded to treatment with KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, according to results from the ZUMA-2 trial presented at the 2019 ASH Annual Meeting. The ZUMA-2 clinical trial treated 74 patients with relapsed/refractory MCL who had received up to five prior lines of therapy, including an anti-CD20 antibody, chemotherapy, and a BTK inhibitor with a single infusion of KTE-X19 at a target dose of 2×106 CAR T cells/kg.(10)
Findings for the first 60 treated patients with a median follow-up of 12.3 months were reported at ASH 2019.
- 93% overall response rate - 67% complete response.
- One-year overall survival of 83%.
- Cytokine release syndrome (CRS) in 91% a median of two days after KTE-X19 administration – all resolved.
Although longer-term follow-up is needed to confirm these early study findings CAR T cell therapy appears to be a promising new treatment option for individuals with relapsed or recurrent MCL. Greater clarity is also being provided regarding two significant side effects associated with CAR T cell therapy.
- Cytokine Release Syndrome (CRS): CRS occurred in 94% of patients with a median time to onset of 2 days (range: 1-12 days) and a median duration of 7 days (range: 2-58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). At the first sign of CRS physicians now institute treatment with tocilizumab and/or corticosteroids.
- Neurologic side effects: Neurologic side effects are reported to occur in 87% of patients, all occurring within the first 8 weeks of therapy. The most common include encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta®. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta®.
While the initial FDA approval is for "transplant ineligible 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 from CAR T of ~ 4% and the 3 year disease free survival are similar to that obtained with a standard stem cell transplant. Moreover the neurologic side effects and CRS are not insignificant. 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.
New Approaches Aim to Enhance CAR T-Cell Therapy
The results of early-phase clinical studies of “second-generation” CAR T cellular immunotherapy products may overcome resistance, reduce side effects and simplify treatment.
CAR T cell therapies are developed by collecting a patient’s own T cells and engineering them to target proteins specific to the surface of their cancer cells and reintroducing these modified T cells back into the patient’s immune system to kill the cancer cells. First-generation CAR T-cell therapies primarily target CD-19, a protein found on the surface of most normal and malignant B cells in B cell cancers such as lymphoma.
Allogeneic CAR T Cell Therapy
Allogeneic derived chimeric antigen receptor (CAR) cell meaning the cells were taken from a non-related healthy donor rather than the patient themselves may have several advantages including;
- The potential to be manufactured in advance and stored for off-the-shelf immediate use which is in contrast to most available CAR T cells which require the use of a patient’s own genetically modified T cells, created through a multi-week manufacturing process.
- Avoidance of CAR T cell cytokine release syndrome and neurotoxicity.
- Lower cost.
Researchers have used allogenic umbilical cord blood-derived chimeric antigen receptor (CAR) natural killer (NK)-cell therapy targeting CD19 in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL), with no major side effects observed. Eleven patients participating in the study had NK cells isolated from donated umbilical cord blood and genetically engineered to express the CAR, which recognizes CD19. The CAR NK cells were also ‘armored’ with IL-15, an immune signaling molecule that is designed to enhance expansion and survival of the cells. (6)
Side effects experienced by participants were primarily related to the conditioning chemotherapy given before cell infusion and were resolved within one to two weeks and no patient required admission to an intensive care unit for management of treatment side effects. Seventy-three percent of patients responded to therapy and seven of those achieved a complete response. Responses to the CD19 allogenic CAR NK cell therapy were evident within one month following infusion, and persistence of CAR T cells was confirmed out to one-year post-infusion. Importantly NO patients experienced cytokine release syndrome or neurotoxicity.
Off-the-Shelf CAR NK Products – FT596
Cellular immunotherapy for B cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities as prescription drugs are.
A product, dubbed FT596, is among the first cellular immunotherapies to be based on off-the-shelf NK cells – the “first line of defense” of the immune system – and is the first cellular immunotherapy to be genetically engineered to contain three active anti-tumor components
FT596 demonstrated comparable ability to kill cancerous white blood cells as standard CAR T cells and, when combined with the drug Rituxan, killed cancerous white blood cells that were no longer responding to standard CAR T-cell therapy due to loss of the CD19 antigen target.
The U.S. Food and Drug Administration (FDA) approved Fate Therapeutics’ Investigational New Drug Application for FT596 in September 2019 and the first patient was treated in March of 2020.
The process of creating FT596 begins with human induced pluripotent stem cells (iPSCs) that are uniquely capable of unlimited self-renewal and can differentiate into more than 200 types of human cells. The iPSCs are genetically engineered, after which a single clone (genetically engineered cell) is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells.
In addition to engineering FT596 to carry a CAR targeting the CD19 protein – which is produced by nearly all B-cell lymphomas and leukemias researchers inserted two other novel proteins: CD16, which boosts and broadens the NK cells’ ability to kill cancer cells, and IL15, which stimulates FT596 to multiply and survive longer.
FT596 has been designed to address two other limitations of CAR T-cell therapy.
- As an off-the-shelf product the time-consuming and costly process that is currently required to treat a patient with CAR T cells is eliminated.
- The addition of the CD16 protein gives FT596 broader therapeutic activity and versatility. In combination with a drug such as Rituxan, FT596 has the potential to lead to deeper and more durable responses and overcome resistance that hampers the long-term efficacy of CAR T-cell therapy. (7,8)
- Locke FL, Ghobadi A, Jacobson CA, et al. [Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1–2 trial](https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18%2930864-7/fulltext). Lancet Oncol. 2019;20(1):31-42.
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