Reem Karmali, MD
The non–Hodgkin lymphoma landscape recently underwent a major transformation, as researchers in the field saw the FDA approval of axicabtagene ciloleucel (axi-cel; Yescarta), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for transplant-ineligible patients with relapsed or refractory disease.
The approval was specifically for patients with large B-cell lymphoma following 2 prior therapies, including those with diffuse large B-cell lymphoma (DLBCL). Additionally, the CAR T-cell therapy is indicated for primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.
The FDA based its decision on data from the phase II ZUMA-1 study, in which axicabtagene ciloleucel was associated with an objective response rate of 82% and a complete response rate of 54%. Thirty-nine percent of patients continued to have a CR after 8.7 months of follow-up.
“The last 5 years have been focused on novel targeted agents, and we are entering an era of cellular immunotherapeutics—and CAR T-cell therapy is something that has a great deal of potential,” said Reem Karmali, MD.
In an interview during the 2017 OncLive®
State of the Science SummitTM
on Hematologic Malignancies, Karmali, assistant professor of medicine (hematology and oncology), Feinberg School of Medicine, Northwestern University, discussed ongoing key trials of CAR T-cell therapy, the chronic safety concerns with the treatment, and what combinations have the most potential.
OncLive: There have been several developments in CAR T-cell therapy over the last few months. What did you share in your presentation?
We went through a little bit of an overview of immunotherapy as a segue to CAR T-cell therapy, and then, with respect to CAR T cells, we talked about the construct itself, its mechanism of action, and then we spoke about some of the key clinical trials for CAR T-cell therapy—specifically focusing on some of the encouraging results we are seeing in DLBCL.
We spoke about 3 of the main multi-institutional pivotal trials that are currently ongoing, including the JULIET study, which is for relapsed/refractory patients with DLBCL who received 2 or more prior lines of therapy. We talked about the ZUMA-1 study which looks at a different CAR T-cell product. Then, we talked about the TRANSCEND study, which looks at a third CAR T-cell product. Essentially, we went through and discussed results for the DLBCL population, the refractory/relapsed DLBCL population, and showed some of the encouraging results that we've managed to get out of these products.
We ended with addressing some of the challenges that we’re facing with respect to CAR T-cell therapy, from a patient selection and toxicity management standpoint. We also went through how we think CAR T-cell therapy may fit into existing modalities of treatment and how it may change treatment paradigms for DLBCL.
We have seen safety challenges thus far with CAR T-cell therapy. What do we know so far?
There are really 2 main toxicities that we are most concerned with. One is cytokine release syndrome (CRS), which is a state of inflammation driven by various cytokines—IL-6 being one of the major cytokines that drive that process.
The other main toxicity that we're concerned with is neurotoxicity. In fact, with some of the earlier products, cerebral edema has been an issue that has led to deaths. More recently, we haven’t seen as many of those specific events occur, but certainly CRS and neurotoxicity are the big issues.
It's not clear what the mechanism is for neurotoxicity. When we think about patient selection, there really needs to be an understanding of the fact that we need to pick patients for CAR T cells that have relatively preserved organ function, so that they can withstand those toxicities with minimal neurological comorbidities. There are some other issues with respect to limitations for CAR T-cell therapy, and that includes the need for adequate hematopoietic reserve so that we can collect adequate CAR T-cell product.