FDA approves the first-ever genetically modified adoptive cell transfer for pediatric acute lymphoblastic leukimia
by Sver Aune
Illustration by Emma Vought
The first adoptive cell transfer (ACT) therapy for the most common childhood cancer was approved by the Food and Drug Administration (FDA) on August 30, 2017, less than two months after a subpanel reviewing the dramatic results from clinical trials unanimously recommended its approval. Prior to FDA approval, there were no clinical treatments other than palliative care for patients with treatment-resistant acute lymphoblastic leukemia (ALL).1
Tisagenlecleucel, a chimeric antigen receptor (CAR) T cell therapy marketed by Novartis as Kymriah™, is the first-ever FDA-approved ACT therapy that incorporates genetic engineering of patients’ own T cells to fight their cancer.1 Kymriah™, also called CTL019 after the cancer antigen it targets, was officially approved for patients up to 25 years of age who have refractory B-cell ALL that has relapsed at least twice. Approval came after dramatic remission rates of 69 and 95 percent were observed in the two main trials reviewed by the FDA. With approval, CTL019 joins checkpoint modulators in the family of immunotherapies that are now considered the fourth pillar of cancer treatment after the historical triad of surgery, chemotherapy, and radiation.
FDA approval opens the way for more equipped hospitals to provide CTL019 and other CAR T cell therapies. Medical centers that have the necessary clinical expertise and infrastructure in place to treat ALL and, importantly, to handle the challenging side effects of adoptive cell treatment, are now working with Novartis to be certified as CTL019 centers so that they can begin to offer the new therapy to their patients.
MUSC Children’s Health is ready, according to Michelle P. Hudspeth, M.D., director of the Division of Pediatric Hematology/Oncology at MUSC Children’s Health. “CAR T cell therapy depends on the very infrastructure that we use every day,” says Hudspeth. “This includes bone marrow transplant coordinators, hemapheresis nurses, cryopreservation technologists, oncology physicians, critical care physicians and oncology, and critical care nurses.”
Therapy for ALL
According to the American Cancer Society, ALL is the most common pediatric cancer in children under the age of 14, making up an estimated 26 percent of all cancers in that age group.3 Roughly 3,100 patients in the U.S. are diagnosed with B-cell ALL every year, but only about 600 or so fall under Kymriah’s™ label.1 ALL is a blood and bone marrow malignancy that develops when blood stem cells make precursor B-cell lymphocytes that do not mature properly and instead proliferate throughout the blood. It is diagnosed with a biopsy of the bone marrow, where normal B-cell lymphocytes mature.
Not surprisingly, ALL is one of the most frequently treated pediatric cancers at MUSC Children’s Health, according to Hudspeth. About 85 percent of children with ALL achieve long-term survival lasting five years following chemotherapy or stem cell transplants, but the remaining patients are unable to achieve remission, leaving them with few treatment options and a median life expectancy of three months.3 CTL019 gives those patients a new option. “Some patients can’t get a stem cell transplant because they have to be in remission to have it work,” says Hudspeth. “Those 10 to 15 percent of patients are incredibly difficult to treat. It’s tremendous that we could have a treatment for those patients.”
CTL019 ingeniously supercharges a patient’s own killer T cells to destroy cancerous B cells, according to Chrystal M. Paulos, Ph.D., associate professor of Microbiology and Immunology and Endowed Peng Chair of Melanoma and Cutaneous T Cell Lymphoma. “Cancer cells downregulate ways in which they can be recognized by natural T cells,” says Paulos. “We can engineer a T cell to recognize a cancer again through a manmade chimeric antigen receptor.”
The immature lymphoid B cells overwhelm T cells in number and are disguised from patients’ immune systems through secretion of anti-inflammatory mediators that subvert the attack from T cells.4
During treatment, some of a patient’s T cells are separated from a blood sample. Then a gene that encodes a chimeric antigen receptor to recognize a molecule called CD19 on the surface of B cells is delivered to the T cells by a retrovirus. Those supercharged T cells are stimulated to multiply and are finally infused back into the patient in much greater number. CARs earn their characterization as chimeras because they are composed of synthetic pieces and different molecular parts, the whole of which does not exist in nature.5
Paulos worked on T cell immunology with Carl H. June, M.D., director of translational research at the University of Pennsylvania, who shepherded the current therapy through the clinical trials that most recently informed FDA approval.6 After Steven A. Rosenberg, M.D., Ph.D., chief of the surgery branch at the National Cancer Institute, first reported the use of CAR T cell therapy in treating cancer in 2012, June reported that the retrovirus used to deliver the gene for the CD19 receptor to T cells was safe and effective, as evidenced by a decade of research encompassing five hundred total patient years.7,8
Juan Carlos Varela M.D., Ph.D., professor of Hematology/Oncology, partners with Paulos to develop strategies using T cells to fight cancer. Together, the two focus on T cell therapies with clinical potential. “All the immunotherapy before was developed for solid tumors, but there wasn’t anything for leukemias and lymphomas until CARs came along,” says Varela.
Varela and Paulos are studying the potential of other CAR T cell therapies in adult ALL and other malignancies. Although CARs can be designed to recognize several different molecules on cancer cells, CTL019 works so well because it targets CD19, a molecule expressed on both normal and cancerous B cells but not on other blood cells. As a result, CAR T cells are very effective at destroying cancerous and healthy B cells in the blood while sparing others. This makes CTL019 attractive for use in other B-cell cancers such as chronic lymphocytic leukemia, the most common leukemia among adults in the U.S.9
“We’re still at the beginning, but to harness this [tumor] response so we can do it in elegant, clean and affordable ways is going to be and exciting new step,” says Paulos.
Novartis is currently choosing which sites outside of those used in CTL019 clinical trials will be the first to treat patients. The adult and pediatric blood and marrow transplantation teams are working to bring Novartis’ CAR-T cell therapy to MUSC to treat pediatric patients. “MUSC is working with Novartis to become a certified site to provide this therapy, and we’re also on our way to being a site for clinical trials for the future of CAR T therapies,” says Varela.
Along with approval for the new therapy, the FDA mandates that facilities providing CTL019 must have a specific “risk evaluation and mitigation strategy” in place to handle cytokine release syndrome, the side effect that occurs in nearly 80 percent of patients.6 Required as part of the strategy is immediate access to tocilizumab, which reduces IL-6, the inflammatory cytokine that is released in the greatest amounts in clinical trials and is believed to be causing the syndrome.8 Fever and life-threatening neurotoxicity can also occur. Also, as of now, patients who receive CTL019 experience a loss of B cells with treatment and must take immunoglobulin infusions monthly for life.
It is still unclear whether insurance payers will cover the treatment, which may cost up to $700,000.10 Still, conducting clinical trials with Novartis and other companies making CAR T cell therapy is a way for the industry to subsidize investment in patients with ALL, according to Varela.
Finally, bringing CAR T therapy to MUSC will hold an additional benefit for pediatric patients with ALL: the nearest centers to provide the therapy — in clinical trials — are Emory University in Atlanta and Duke in North Carolina. “We are here to make sure patients get whatever therapy they need in South Carolina,” says Hudspeth. “It has a major impact for the child and their family to get treatment close to home.”
***Update: On October 18, the FDA approved a second CAR T therapy — axicabtagene ciloleucel (Yescarta; Kyte Pharma, a Gilead Company) — to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment.
1 FDA News Release. fda.gov. 2017. website. Retrieved from fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm.
3 Ward E. 2014. American Cancer Society. Childhood and adolescent cancer statistics [PowerPoint slides].
10 OncLive.com. Hagen T. 2017. website. Retrieved from http://www.onclive.com/web exclusives/novartis-sets-a-price-of-475000-for-car-tcell-therapy.