ASH Clinical News ACN_3.12s_OCT_SUPP | Page 6

FEATURE Entering A New Era of Immunotherapy The U.S. Food and Drug Administration’s (FDA) approval of the first chimeric antigen receptor (CAR) T-cell therapy represents a paradigm shift in the treatment of hematologic malignancies, but questions remain about its rollout. On August 30, 2017, the FDA approved the first gene therapy in the United States: Tisagenlecleucel (Kymriah, Novartis) is a CD19-directed CAR T-cell therapy approved for certain pedi- atric and young adult patients with relapsed or refractory B-cell precursor acute lymphocytic leukemia (ALL). 1 “These are patients who have tried at least one or two prior therapies, sometimes including bone marrow (BM) transplanta- tion, and none of these therapies are working,” explained Jae Park, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, who is investigating CD19-directed CAR T-cell therapies in B-cell malignancies. “In this setting, CAR T cells can induce complete responses (CRs) in the range of about 80 percent, which is quite remarkable and higher than anything we have seen in this setting.” With tisagenlecleucel, the high remission rates were achieved within three months of a one-time infusion. 2 Like many of the other “hot” cancer therapies, CAR T-cell therapy is an immunotherapy. However, unlike immune checkpoint inhibitors, CAR T-cell therapies harness the power of each patient’s individual immune system, making it the “ultimate in personalized therapy,” according to Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy at the University of Penn- sylvania’s Perelman School of Medicine in Philadelphia. ASH Clinical News spoke with Drs. Park and Levine about tis- agenlecleucel, how CAR T-cell therapies work, and the challenges of putting them into practice. The CAR Pipeline “In patients with cancer, immune T cells are not successfully sup- pressing cancer cells,” Dr. Park said, offering a simple explanation of how and why CAR T-cell therapy works. “With CAR T-cell therapy, we take T cells from the patient and modify them to express a new artificial receptor engineered to recognize cancer cells. We then infuse those cells back into the patient, where they are better able to recognize and start killing off cancer cells.” Tisagenlecleucel, like most other CAR therapies furthest in the pipeline, modifies T cells to target cells that have the CD19 antigen on their surface. It is approved for patients with ALL, but CAR T-cell therapies are being investigated in other hematologic malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). The FDA accepted another CD19-directed candidate, axicabtagene ciloleucel, for priority review on May 26, 2017. Submission of the biologics license application was supported by data from the phase II ZUMA-1 trial of patients with refractory, aggressive NHL. After a median follow-up of 8.7 months, the objective response rate after a single infusion of axicabtagene ciloleucel was 82 percent, including a CR rate of 39 percent. 3 4 Focus on Immunotherapy “This therapy is being looked at specifically in patients with diffuse large B-cell lymphoma (DLBCL), which is more common than ALL,” said Dr. Park, adding that the FDA has set a Prescrip- tion Drug User Fee Act target action date of November 29, 2017. Juno Therapeutics also has several CAR T-cell therapies under investigation, but early safety results from those trials