Frederick Locke, MD
KTE-C19, an engineered autologous T-cell therapy, has demonstrated improved response in patients with refractory aggressive non-Hodgkin lymphoma (NHL), according to data from the ongoing phase I/II ZUMA-1 study presented at the 2015 ASH Annual Meeting.
Thus far, seven patients received KTE-C19 at a target dose of 2 x 106
(minimum 1 x 106
) anti-CD19 chimeric antigen receptor (CAR) T cells per kg of body weight after a fixed-dose conditioning chemotherapy regimen.
Seventy-one percent of patients experienced a response, with 4 complete remissions (CRs) and 1 partial remission observed, according to Kite Pharma, the company manufacturing the therapy. All CRs were observed at 1 month and 3 subjects had ongoing CRs after 3 months.
In December, Kite reported that the FDA had granted KTE-C19 breakthrough therapy designation status for use in patients with aggressive NHL—specifically, the 3 NHL subtypes examined in ZUMA-1: refractory diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, and transformed follicular lymphoma.
To learn more about the potential for KTE-C19 in NHL, OncLive
spoke with study lead study author Frederick Locke, MD, a medical oncologist in the Department of Blood and Marrow Transplant at Moffitt Cancer Center, and an assistant professor of Oncology at the University of South Florida.
OncLive: What can you share about KTE-C19?
: KTE-C19 is a Kite Pharma¬–manufactured autologous cell therapy product. After cells are collected from patients with refractory aggressive NHL, they are shipped to the Kite Pharma manufacturing facility and the gene for the chimeric antigen receptor is inserted into the T cells. This manufacturing process is the same process that is utilized at the National Cancer Institute, where this therapy was developed. After we send the cells to Kite Pharma, it takes approximately 2 weeks until we get the cells back. All patients who had cells collected had an adequate number of CAR T cells manufactured. Moreover, all patients who were treated received a standardized dose and schedule of fludarabine and cytoxan.
What is significant about this study?
This study is important because it is a multicenter study conducted at major cancer centers that do not necessarily have any experience utilizing CAR T-cell therapy. Secondly, we showed that this therapy could be successful for aggressive refractory lymphomas. It is important to note that, in the ongoing phase II study and this phase I portion, patients were selected with refractory aggressive lymphomas who did not respond to their last therapy. Patients had either stable disease or progressive disease after their last therapy, or they relapsed shortly after autologous hematopoietic stem cell transplant.
Were there any concerning toxicities?
Seven patients were treated, and this therapy was deemed safe. Eighty-six percent of patients who were treated developed cytokine release syndrome (CRS) and one patient had grade 4 CRS. This typically consists of high fevers, occasional low blood pressure, and, sometimes, hypoxia. In cases where it was felt that this was severe, steroids could be utilized. All patients on this treatment did receive tocilizumab, an anti–IL-6 receptor monoclonal antibody, so that was generally how the CRS was managed.
One hundred percent of patients developed neurologic toxicities do to KTE-C19 therapy. One of those was a grade 3 toxicity and 1 was a grade 4 neurotoxicity. One patient did die on study due to intracranial hemorrhage and it was felt by the investigators that this was not due to KTE-C19 therapy, as this patient had very low platelets and had been heavily pretreated.
For neurologic toxicities, many patients received dexamethasone for treatment; however, it is unclear if this has an effect on the development or the history of neurologic toxicities.
What are the next steps planned for this research?
In the setting of refractory aggressive lymphomas, it will be critical to know if these response rates hold up in larger cohorts and if the duration of these responses is prolonged. Diffuse large B-cell lymphoma is a potentially curable malignancy. We don’t know if these therapies will be curable or not, but the expected response to chemotherapy in this patient population is 0% to 23%, so this is a population that we really need to do better work in. We hope that this therapy will provide that.
Do you envision these types of treatments being used in other settings?
This particular therapy targets CD-19. This is a target that is expressed in B-cell malignancies, which includes aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma. It also includes acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL). Currently, Kite Pharma has 3 trials open for adult patients: one for refractory aggressive leukemia, another for ALL, and a third for MCL. All 3 of those are open and enrolling patients.
Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 clinical results of the ZUMA-1 (KTE-C19-101) study: a phase 1-2 multi-center study evaluating the safety and efficacy of anti-cd19 car t cells (KTE-c19) in subjects with refractory aggressive non-hodgkin lymphoma (NHL). Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 3991.