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Chimeric antigen receptor T cells exhibit efficacy in advanced lymphoma
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CHICAGO — Treatment with T cells genetically modified to express chimeric antigen receptors targeting CD19 induced remission in patients with advanced B-cell lymphoma when administered with low-dose chemotherapy, according to study results presented at the ASCO Annual Meeting.
The use of chimeric antigen receptor (CAR) T cells may become a standard of care for advanced lymphoma in the near future, according to James N. Kochenderfer, MD, investigator in the experimental transplantation and immunology branch of the NCI’s Center for Cancer Research.
James N. Kochenderfer
“T cells that are genetically modified to express CARs targeting CD19 have significant activity against B-cell malignancies,” Kochenderfer said during his presentation. “In almost all clinical trials of anti–CD19 CAR T cells, the T-cell infusions are preceded by chemotherapy, because depletion of the recipient leukocytes has been shown to enhance the activity of adoptively transferred T cells.”
Kochenderfer and colleagues previously reported data from patients treated with CAR T cells and high-dose chemotherapy.
In the current analysis, researchers assigned 22 patients with advanced lymphoma to low-dose conditioning chemotherapy, followed by anti-CD19 CAR T-cell infusion.
Nineteen patients had diffuse large B-cell lymphoma (DLBCL). Two patients had follicular lymphoma and one patient had mantle cell lymphoma.
Eighteen patients received daily cyclophosphamide (300 mg/m2 per day) for 3 days; the remaining four patients received a dose of 500 mg/m2 on the same schedule. All patients received fludarabine (30 mg/m2) on the same schedule.
Patients received a single dose of CAR T cells 2 days after completing chemotherapy, after which the researchers analyzed blood CAR T cells and serum cytokines.
The overall response rate for the entire cohort was 73%, with an ORR of 68% in the DLBCL patient population.
Eight patients with DLBCL achieved a complete response, as did all patients with follicular lymphoma and mantle cell lymphoma.
Five patients with DLBCL achieved a partial response, with two patients experiencing stable disease. Four patients experienced progressive disease.
Ten patients’ responses remained ongoing at the time of reporting, with durations of response ranging from 1 month to 20 months.
All but four patients had chemotherapy-refractory lymphoma or relapsed lymphoma after autologous stem cell transplantation.
All patients developed fevers, and 55% (n = 12) experienced grade 3 or grade 4 neurological toxicities. However, all toxicities completely resolved, usually in less than 2 weeks, Kochenderfer said.
Patients had a median CAR–positive cell level of 47 L (range, 4-1,217). Those who achieved complete or partial responses had higher peak blood CAR–positive cell levels than patients who experienced stable or progressive disease.
Mean serum interleukin-15 levels significantly increased after chemotherapy conditioning (4 pg/mL vs. 32 pg/mL; P < .0001).
“Anti–CD19 CAR T cells are now involved in multicenter trials,” Kochenderfer said. “They will probably become an important part of lymphoma therapy in the future, particularly to salvage the patients who are refractory to chemotherapy and have very few other options.” – by Cameron Kelsall
Reference:
Kochenderfer J, et al. Abstract LBA3010. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: The NIH funded this study. Kochenderfer reports institutional research funding from Bluebird Bio and Kite Pharma, as well as a patent agreement with Bluebird Bio. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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John P. Leonard, MD
This abstract provides additional data on chimeric antigen receptor (CAR) T cells for the treatment of aggressive lymphomas. CAR T cells are very exciting, receiving much attention, and there are a lot of data coming out on their use in lymphoid malignancies. One of the challenges is to take them forward in a way that definitively demonstrates their value compared with other treatments. This study included data from 22 patients and showed that a regimen of fludarabine and/or cyclophosphamide in a nonmyeloablative fashion, in addition to CAR T cells, could induce meaningful remissions in patients with diffuse large B-cell lymphoma (DLBCL). A few other aggressive subtypes were included, but most of the patients in this report had DLBCL. A majority of patients included in this study had a response, which is exciting, because it shows that we can observe a high response rate when patients are treated with CAR T cells. Further, the chemotherapy regimen used was attenuated in dose, so we can attribute the effect primarily to the CAR T cells and less so to the chemotherapy.
These represent additional data that show that this treatment regimen has potential in the treatment of patients with resistant, aggressive lymphoma. As far as follow-up is concerned, we need additional studies with larger groups of patients, with longer follow-up periods, to see if these responses are going to be durable. That is going to be quite important to see in much larger patient populations. We also need to address the critical fact that there is an inherent selection bias in CAR T-cell therapy. There are patients who are not candidates for this type of treatment because of their age and comorbidity burden, or because they have rapidly aggressive/growing disease. Because there is an inherent delay of a few weeks required to get a patient enrolled and get them CAR T cells (and sometimes longer to even be able to be considered for a spot on a trial), some patients with aggressive lymphoma are left out because they cannot wait that long for therapy. So, there is an inherent bias toward patients who are healthy, and those which have more favorable (less rapidly growing or symptomatic) disease allowing them wait a little longer for treatment.
That being said, the lymphoma community remains excited, and it is safe to say there is a good chance this treatment will be more widely used in the future.
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