The U.S. Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) from Kite Pharma, a division of Gliead Sciences, and granted Priority Review designation for KTE-X19, an investigational chimeric antigen receptor (CAR) T-cell therapy for the treatment of adult patients with relapsed or refractory Mantle Cell Lymphoma (MCL).
CAR T-cells have yielded unprecedented efficacy in B cell malignancies, and, as a result, dramatically shifted the landscape of treatment options, most notably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate.
KTE-X19 is an investigational agent, autologous, anti-CD19 CAR T-cell therapy currently in Phase I/II clinical trials in the treatment of patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).
Biologics License Application
Kite’s BLA for KTW-X19 is supported by data from the single-arm, open-label, multicenter Phase II ZUMA-2 trial (NCT02601313), involving 74 enrolled/leukapheresed adult patients (≥18 years old) with MCL whose disease is refractory to or has relapsed following up to five (5) prior lines of therapy, including anthracycline or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and the BTK inhibitors ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) or acalabrutinib (Calquence®; AstraZeneca). All participants had also an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
For 3 days prior to KTE-X19 therapy the participating patients underwent conditioning with a chemotherapy regimen of cyclophosphamide 300 mg/m2 per day and fludarabine 30 mg/m2. In addition, the study protocol allowed patients to receive bridging therapy during the CAR T-cell manufacturing process, according to the investigator’s discretion. This could include ibrutinib, acalabrutinib, or dexamethasone. After completing of the manufacturing process, patients received a single infusion of KTE-X19 at a target dose of 2×106 CAR T-cells/kg. Following infusion, tumor response was first assessed 28 days after treatment.
The trial results showed that 93% of patients responded to a single infusion of , including 67% of patients achieving a complete response, as assessed by an Independent Radiologic Review Committee (IRRC; median follow-up of 12.3 months).
In the safety analysis, Grade 3 or higher cytokine release syndrome (CRS) and neurologic events were seen in 15% and 31% of patients, respectively. No Grade 5 CRS or neurologic events occurred. Detailed findings from this trial were presented earlier during an oral session at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition held on December 7 – 10, 2019 in Orlando, Florida. 
“There is a significant need for novel treatment options for patients with MCL, especially those whose disease has progressed following several lines of previous therapy,” noted Michael Wang, MD, ZUMA-2 Lead Investigator, and Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.
“The impressive response rates observed with KTE-X19 support its potential as the first cell therapy for people living with MCL,” he added.
With a median follow-up of 12.3 months (range: 7.0 to 32.3 months) at the time of data cutoff, 57 percent of patients remained in an ongoing response. Of the first 28 patients treated (minimum follow-up of 24 months), 43 percent were alive and remained in continued remission without additional therapy. The 12-month estimates of progression-free survival (PFS) and overall survival (OS) were 61% and 83%, respectively. The median duration of response, PFS and OS were not yet reached.
Mantel cell Lymphoma
Mantle cell lymphoma is a rare form of non-Hodgkin lymphoma (NHL) that arises from cells originating in the “mantle zone” of the lymph node and typically affects men over the age of 60.
“Despite recent advances, patients with relapsed/refractory mantle cell lymphoma currently face a significant lack of effective treatment options once their disease no longer responds to currently available therapy,” said Ken Takeshita, MD, Kite’s Global Head of Clinical Development. “Based on the encouraging results for KTE-X19, we are eager to continue discussions with the FDA on how to bring this innovative treatment to these patients who may benefit from CAR T therapy.”
The Prescription Drug User Fee Act (PDUFA), or target action date, is August 10, 2020.
In the manufacturing of KTE-X19, Kite uses the XLP™ manufacturing process that includes the T-cell selection and lymphocyte enrichment. Lymphocyte enrichment is a necessary step in certain B-cell malignancies in which circulating lymphoblasts are a common feature.
The manufacturing process of KTE-X19 consists of an anti-CD19 single-chain variable fragment with a CD3 ζ (zeta) T-cell activation domain and a CD28 signaling domain. During the manufacturing process, circulating tumor cells (CTC) are separated from autologous immune cells. This approach differentiates KTE-X19 from axicabtagene ciloleucel (Yescarta®; Gilead/Kite)
KTE-X19 has been granted Breakthrough Therapy Designation by the FDA and Priority Medicines (PRIME) designation by the EMA for relapsed or refractory MCL. The European Medicines Agency (EMA) recently validated the Marketing Authorization Application for KTE-X19 in the European Union.
If approved, Kite could be the first company with multiple commercialized CAR T-cell therapies.
A Phase 2 Multicenter Study Evaluating Subjects With Relapsed/Refractory Mantle Cell Lymphoma (ZUMA-2) – NCT02601313
 Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53. Published 2017 Feb 21. doi:10.1186/s13045-017-0423-1
 Sermer D, Brentjens R. CAR T-cell therapy: Full speed ahead. Hematol Oncol. 2019;37 Suppl 1:95–100. doi:10.1002/hon.2591
 Wang ML, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study. Abstract #754. Presented at the 2019 ASH Annual Meeting, December 9, 2019; Orlando, FL.