How KTE-C19 works
NHL is a group of closely related blood cancers that are caused by the abnormal behavior and fast growth of immune cells, or lymphocytes. There are many different types, based on the type of lymphocyte the cancer started in, the behavior of the cancer, and whether certain proteins are expressed on the cancer cell surface.
KTE-C19 is a type of immunotherapy; it uses the body’s own immune system to fight the cancer. Normally, a type of lymphocyte, called a T-cell, can detect and destroy abnormal cells to protect the body. However, in cancer, the immune system is often unable to recognize the cancer cells or is too weak to have an effect.
By genetically modifying the patient’s own T-cells to express a CAR, the modified T-cells can be directed to attack cancer cells expressing the CD19 protein.
CAR is a protein that has part of an antibody that is designed to interact specifically with CD19, which can activate an attached signaling domain. When CD19 binds to the CAR, a message is passed onto the T-cell, activating it and directing it to kill the cancer cell.
To produce KTE-C19, the patient’s T-cells are first isolated from a blood sample. These are modified and expanded so that there are enough T-cells to treat the patient. The modified T-cells are then returned to the patient’s body in an intravenous infusion, so they can target and kill the cancer cells.
KTE-C19 in clinical trials
KTE-C19 is currently being investigated as a treatment for several types of NHL in seven clinical trials and two pre-clinical studies, as part of the ZUMA program.
The Phase 1/2 ZUMA-1 trial (NCT02348216) is assessing the safety, efficacy, and dosage of KTE-C19 in patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) that has come back (relapsed) or cannot be treated with standard therapies (refractory).
Results from seven DLBCL patients treated in the Phase 1 portion of ZUMA-1 have been published in the journal Molecular Therapy. Of the seven patients, four (57 percent) achieved complete remission (CR), where there are no symptoms of the cancer. Three of these patients were still in CR over 12 months later. In these patients, KTE-C19 was still present in the body at the time of follow-up.
Topline primary results of the ZUMA-1 Phase 2 trial were announced in February 2017. A total 77 patients with DLBCL and 24 with TFL or PMBCL were treated. At six months, 31 percent of DLBCL patients and 54 percent of TFL/PMBCL patients achieved CR. The study met its primary endpoint with an overall response rate of 82 percent after a single KTE-C19 infusion. Kite reported that three deaths occurred during the study, but they were not related to KTE-C19 treatment.
The Phase 1/2 ZUMA-3 (NCT02614066) trial is investigating KTE-C19 in an estimated 75 patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). At the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Kite announced that 73 percent of patients treated so far in the Phase 1 trial achieved CR. However, one patient experienced a fatal cytokine release syndrome. Kite aims to initiate the Phase 2 trial in 2017.
ZUMA-4 (NCT02625480) is a Phase 1/2 clinical trial to test KTE-C19 in 75 pediatric/adolescent patients, ages 2 to 21, with relapsed/refractory ALL. In May 2017, an update for the first four treated patients was presented at the 22nd Congress of the European Hematology Association showing that the safety profile has been acceptable and that recruitment is continuing.
The Phase 2 ZUMA-5 trial (NCT03105336) aims to assess KTE-C19 as a treatment for indolent B-cell NHL that has relapsed or is resistant to standard therapy. The first patient of an estimated 50 received KTE-C19 on Aug. 2, 2017.
KTE-C19 was designated a breakthrough therapy for DLBCL, TFL, and PMBCL by the U.S. Food and Drug Administration (FDA) in December 2015. KTE-C19 was also the first treatment to be granted access to the European Medicines Agency’s (EMA) new priority medicines (PRIME) regulatory initiative in June 2016, which aims to support and accelerate the development of therapies for diseases with an unmet medical need.
Kite submitted a biologics license application (BLA) for KTE-C19 to the FDA based on the results of the ZUMA-1 trial in March 2017. The FDA granted the BLA priority review status, with an expected action date of Nov. 29, 2017.
Kite followed this with a marketing authorization application (MAA) to the EMA on July 31, 2017.
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