This year, Oncology Times debuted an exciting contest designed to recognize the wonderful research, dedication, and dramatic impact on patients that occur every day in oncology. The Excellence in Oncology initiative garnered submissions from all areas of the field, highlighting research and clinical programs in a variety of specialties and cancer centers. In this issue, we are excited to showcase the winning research of Sattva Neelapu, MD, and Frederick Locke, MD, focusing on CAR T-cell therapy for adult patients with diffuse large B-cell lymphoma. Watch for additional winners to be to be highlighted throughout the year.
Advances in gene therapy have provided medical oncologists and research scientists with the tools they need to develop adoptive approaches to fighting cancer, such as chimeric antigen receptor (CAR) T-cell therapy, which enlists a patient's own immune system into the battle.
A new CAR T-cell therapy, axicabtagene ciloleucel (axi-cel), is the first approved by the FDA for adult patients with an aggressive form of refractory non-Hodgkin lymphoma (NHL) called diffuse large B-cell lymphoma, and whose cancer did not respond to prior chemotherapy. Axi-cel was FDA approved Oct. 18, 2017.
For the axi-cel CAR T-cell therapy, blood is removed from patients and sent to a centralized lab where scientists extract the T cells through leukapheresis and then they add new receptors to them. The reprogrammed T cells are then returned to the facility and re-infused into the patient in a single treatment.
Armed with the new CAR receptors, the patient's modified T cells begin to hunt and kill lymphoma cells by identifying a specific antigen (CD19) on their surface. The T cells only target the cancerous cells, and so unlike chemotherapy, axi-cel does not harm healthy dividing cells throughout the body.
The results from the ZUMA-1 study showed measurable responses in 82 percent of 108 patients administered axi-cel, and complete responses in 54 percent. Fifty-six percent of patients were still alive 15 months following the CAR T-cell therapy, and some remained cancer-free 2 years following treatment.
“Many patients' lymphoma tumors melted away within a month,” said one of the study's lead researchers, Frederick Locke, MD, Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, in announcing the results. “The long-term follow-up results of the ZUMA-1 trial show that axi-cel remissions can last years—and these are patients that did not respond to chemotherapy.”
Locke co-led the 22-institution ZUMA-1 trial with Sattva Neelapu, MD, Professor of Lymphoma & Myeloma, at The University of Texas MD Anderson Cancer Center in Houston. In recognition of their groundbreaking research, Locke and Neelapu have been named the winners of the inaugural Oncology Times Excellence in Oncology award.
“As an oncologist, and as a researcher who has long believed in the potential of immunotherapy, it is extremely gratifying to be part of the development of this product that is likely to impact the lives of many patients across the globe,” Neelapu said, adding he was “humbled and honored” by the recognition.
Neelapu was also quick to note the contributions of others who were instrumental in axi-cel earning FDA approval, including researchers who've spent 2 decades working on the CAR T-cell approach; the investigators and hospital staff who participated in the ZUMA-1 trial; Kite Pharma, which sponsored the ZUMA-1 trial and manufactured the product; “and, most importantly, the patients and caregivers for participating in the clinical trial.”
In an interview with Oncology Times, Neelapu shared insights into the ZUMA-1 study and the development and promise of axi-cel.
“The early success observed at single institution trials with CD19-specific CAR T-cell therapy prompted us to investigate this approach in the pivotal multicenter ZUMA-1 trial in lymphoma patients with the most unmet need,” he said, in describing the impetus for the landmark study.
Prior to the ZUMA-1 study, Neelapu said the CD19-specific CAR T-cell therapy was only tested at single institutions. The axi-cel product was manufactured on-site and only a handful of investigators had experience in managing the side effects associated with the therapy.
“The ZUMA-1 study was the first multicenter study to investigate CAR T-cell therapy in lymphoma,” Neelapu noted. “It demonstrated that centralized manufacturing is feasible and with appropriate training of health care providers and development of toxicity management algorithms, this therapy can be administered safely to patients at sites previously not experienced in this approach.”
In the ZUMA-1 study, the CD19-specific CAR T-cell product was manufactured for 99 percent of the patients, even in patients who had received multiple lines of chemotherapy, said Neelapu. “In fact, the product could not be manufactured in only one case,” he said, adding, “The product also could be generated fairly rapidly with a turnaround time of only 17 days.”
Safe & Effective
The ZUMA-1 study findings also showed the CD19-specific CAR T-cell therapy is highly effective, with an overall response rate of 82 percent and a complete response rate of 58 percent in patients who have highly chemorefractory disease, Neelapu noted.
“This type of response rates is unprecedented in this patient population,” he explained. “Standard chemotherapy has an overall response rate of only 26 percent and a complete response rate of 7 percent in this patient population.”
Responses to axi-cel also are durable and ongoing beyond 1 year in about 40 percent of the patients, Neelapu said. “Moreover, median survival is estimated to be 18 months for these patients treated with axi-cel therapy compared with approximately 6 months with standard chemotherapy,” he added.
Axi-cel does have some side effects, most commonly fever and confusion. The ZUMA-1 study also reported three patient deaths related to adverse effects. Two of the patients had cytokine release syndrome due to axi-cel, while one experienced a pulmonary embolism unrelated to the therapy.
“There is a misconception that this therapy is very toxic. In fact, it is not,” Neelapu insisted. “Most patients develop only grade 1 or grade 2 side effects in the form of fever, and sometimes transient confusion. A small percentage of patients may need management in the intensive care unit, but the side effects are completely reversible within 1-2 weeks.
“Moreover, the therapy only requires a one-time infusion of CAR T cells, as these are like a living drug and can persist long-term in the body,” Neelapu continued. “Many patients, even those in their 60s or 70s, can go back to their work or usual activities by 1 or 2 months after receiving this therapy. In contrast, traditional chemotherapy or stem cell transplantation involves multiple cycles of therapy or takes 3-6 months for the patients to recover from their side effects.”
Hope for the Future
In terms of its clinical implications, Neelapu noted that axi-cel not only is the first therapeutic product ever approved by the FDA for the treatment of patients with aggressive non-Hodgkin lymphoma, but also the first that “offers hope for patients who otherwise have no effective treatment options.”
“On an average, it appears to prolong survival by at least 1 year for patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma,” he explained. “More importantly, it induces long-term remission and possibly a cure in about 40 percent of the patients. Therefore, this therapy is a major advance in the treatment of aggressive B-cell lymphomas.”
Looking ahead, Neelapu noted that the axi-cel therapy currently is being tested in other B-cell malignancies, including various types of lymphoma, such as follicular and mantle cell lymphoma, as well as leukemias, such as acute lymphoblastic leukemia and chronic lymphocytic leukemia.
One study is also testing axi-cel in an earlier stage of the disease process, specifically the second-line setting (after the relapse) in a randomized trial head-to-head with autologous stem cell transplantation in aggressive B-cell non-Hodgkin lymphoma, he noted.
“We need to better understand the mechanisms of resistance and failure with this therapy so that we can further improve the efficacy of this approach,” Neelapu said. “One approach being investigated is to combine axi-cel with PD-1 or PD-L1 antibody to overcome immune suppression in the tumor microenvironment. Another approach is to target other antigens besides CD19 with CAR T-cell therapy as some tumors become resistant due to loss of CD19.”
Such findings would be extremely satisfying to Neelapu, whose clinical interest has long been in the field of lymphomas and patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma who have had a major unmet need with no FDA-approved therapeutic agent even after decades of research.
“This is really an exciting time to be in cancer research, especially in the field of immunotherapy,” he concluded. “I hope our collective efforts will continue to advance cancer therapies and save many more lives of our patients.”
Chuck Holt is a contributing writer.
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