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CAR T-cell therapy approved for B-cell lymphomas may save ‘thousands of lives’ in next few years
The FDA’s decision this past summer to approve the first chimeric antigen receptor T-cell therapy represented a watershed moment for cancer care.
However, the second such approval — announced last month — could have a far more significant impact, according to leaders in the field.
The agency on Oct. 18 approved axicabtagene ciloleucel (Yescarta; Kite, Gilead), a chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory large B-cell lymphoma who underwent two or more lines of systemic therapy.
The indication includes patients with diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL that arises from follicular lymphoma. The agent is not indicated for the treatment of patients with primary central nervous system lymphoma.
The decision came less than 2 months after the FDA approved tisagenlecleucel (Kymriah, Novartis), a CAR T-cell therapy for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
“The [tisagenlecleucel approval] impacted a relatively small number of pediatric and young adult patients,” David Maloney, MD, PhD, medical director of cellular immunotherapy at Fred Hutchinson Cancer Research Center and medical director of Bezos Family Immunotherapy Clinic at Seattle Cancer Care Alliance, said in a statement. “[The axicabtagene ciloleucel] 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.”
‘Impressive’ results
Both tisagenlecleucel and axicabtagene ciloleucel are comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells.
Each patient’s T cells are collected and sent to a manufacturing center, where they are re-engineered to include a new gene that contains a CAR that directs T cells to target and kill CD19-expressing cancer cells. The modified cells then are infused back into the patient.
The FDA based its approval of axicabtagene ciloleucel in part on data from the ZUMA-1 trial, designed to evaluate the therapy in 101 adults with relapsed or refractory large B-cell lymphoma.
Seventy-two percent of patients treated with a single infusion responded to therapy, and 51% (95% CI, 41-62) of patients achieved complete response.
At a median follow-up of 7.9 months, median duration of response among patients who achieved complete remission had not been reached (95% CI; 8.1-not estimable).
“With CAR T therapy, we are re-engineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” co-lead investigator Frederick L. Locke, MD, vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center, said in a Gilead-issued press release. “Many of the patients [who] received CAR T therapy had already relapsed several times with traditional treatments, such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy, many patients are in remission for months.”
Thirteen percent of patients experienced grade 3 or higher cytokine release syndrome and 31% had neurologic toxicities.
The most common grade 3 or worse toxicities included febrile neutropenia, fever, cytokine release syndrome, encephalopathy, infections with unspecified pathogens, hypotension, hypoxia and lung infections.
Serious adverse reactions — which occurred in 52% of patients — included cytokine release syndrome, neurologic toxicity, prolonged cytopenias and serious infections.
“The current CAR T-cell therapies need to become more effective, more affordable and safer,” Maloney said. “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 [and] occasionally fatal side effects.”
Because fatal cases of cytokine release syndrome and neurologic toxicity occurred, the FDA approved axicabtagene ciloleucel with a risk evaluation and mitigation strategy.
Hospitals and clinics that dispense the therapy must receive special certification that involves training staff to recognize and manage cytokine release syndrome or nervous system toxicities. Patients also must be informed about serious adverse events and the need to return to their treatment site upon the development of serious symptoms.
“[This] is an important day for patients with relapsed or refractory large B-cell lymphoma who have run out of options and have been waiting for new treatments that may help them in their fight against cancer,” John Milligan, PhD, president and CEO of Gilead Sciences, said in a company-issued press release. “With the combined innovation, talent and drive of the Kite and Gilead teams, we will rapidly advance cell therapy research and aim to bring new options to patients with many other types of cancer.”
Arie Belldegrun, MD, FACS, founder of Kite, called the FDA’s approval of Yescarta “a landmark” for patients with relapsed or refractory large B-cell lymphoma.
“This approval would not have been possible without the courageous commitment of patients and clinicians, as well as the ongoing dedication of Kite’s employees,” Belldegrun said in the release. “We must also recognize the FDA for their ability to embrace and support transformational new technologies that treat life-threatening illnesses. We believe this is only the beginning for CAR T therapies.”
Promising to practical
The approval of axicabtagene ciloleucel represents another milestone in the development of a “new scientific paradigm” for the treatment of serious diseases, according to FDA Commissioner Scott Gottlieb, MD.
“In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer,” Gottlieb said in an agency-issued press release. “This approval demonstrates the continued momentum of this promising new area of medicine and we’re committed to supporting and helping expedite the development of these products.”
Gottlieb said the FDA intends to release a comprehensive policy that will outline how it plans to support the development of cell-based regenerative medicine.
“That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR T cells and other gene therapies,” Gottlieb said. “We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.” – by Kristie L. Kahl
Perspective
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The early results we have seen with CAR T cells in the past 5 years are easily the most potent therapy ever tested for these patients, with 30% to 40% achieving and maintaining complete remission for months, possibly years. Some of the earliest patients treated more than 5 years ago are still in remission and appear to be cured. The success is a testament to the many scientists, physicians and others who developed this almost-science-fictional therapy.
The process removes immune, or T, cells from a patient and inserts a synthetic CAR gene — actually a chimera of five genes “cut and pasted” together — into the T cells to create CAR T cells that are reinfused into the patients 2 to 3 weeks later. Back in the patient, the CAR allows the T cells to specifically target and then eliminate the cancer cells, just as T cells would normally target and eliminate virus-infected cells.
The activation of these anticancer T cells can sometimes hyperactivate them, making them release chemicals, or cytokines, which cause a sepsis-like condition that can be extremely dangerous. These effects generally occur only in the first 2 weeks after the infusion. Thereafter, the CAR T cells can live inside the patient for months or years, continuing to fight any residual cancer cells; hence their description as a “living medicine.”
Unquestionably, the results are transformational for how we treat these patients and, at best, will transform an incurable disease setting into a potentially curable one. The remaining question is how we will be able to expand this approach to treat patients with other types of lymphoma, leukemia and myeloma, and — eventually — common cancers like breast, prostate and lung cancers.
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