Σάββατο, 1 Απριλίου 2017

IL-15 LEVEL PREDICTIVE FACTOR FOR RESPONSE O CAR-T CELL THERAPY

As reported by Kochenderfer et al in the Journal of Clinical Oncology, remission in patients with advanced lymphoma induced by treatment with chimeric antigen receptor (CAR) T cells targeting CD19 (CAR-19) is associated with elevated serum interleukin-15 (IL-15) levels.
Study Details
The study involved 22 patients with advanced lymphoma who received a single infusion of CAR-19 T cells 2 days after a low-dose conditioning regimen of cyclophosphamide plus fludarabine. A total of 19 patients had diffuse large B-cell lymphoma, 2 had follicular lymphoma, and 1 had mantle cell lymphoma.
Remission Rate
Remission was achieved in 16 patients (73%), including complete remission in 12 (55%). In patients with diffuse large B-cell lymphoma, the overall remission rate was 68%, with complete remission in 47%. Complete remissions were ongoing in 11 patients at the time of reporting, with a median duration of response of 12.5 months. No patient with ongoing remission received any additional antilymphoma therapy.
Association With IL-15
The low-dose chemotherapy conditioning regimen was associated with depletion of blood lymphocytes and increased serum IL-15 levels. The number of blood CAR-positive cells peaked at a median of 8.5 days after infusion; median peak CAR-positive cell levels were 98/µL in patients who achieved remission vs 15/µL in those who did not (P = .027). Higher peak serum IL-15 levels were associated with higher peak CAR-positive cell levels (P = .001) and with remission (P < .001).
The median day of peak IL-15 levels was day 2 after CAR T-cell infusion. However, patients with remission had higher IL-15 AUC values from day 5 before treatment to day 14 after treatment; on the day of CAR T-cell infusion, median IL-15 levels were higher in patients who subsequently achieved remission (30 vs 16 pg/mL, P = .010). As stated by the investigators, “This suggests that the environment that CAR T cells enter upon infusion is a determinant of treatment outcomes.”
Neurologic Toxicity
Grade 3 or 4 neurologic toxicity, including dysphasia, confusion, and tremor, occurred in 55% of patients, with complete resolution observed in all. Higher peak levels of IL-15 were associated with an increased risk of grade 3 or 4 toxicity, as were higher peak serum levels of granzyme B and IL-10.
The investigators concluded: “CAR-19 T cells preceded by low-dose chemotherapy induced remission of advanced-stage lymphoma, and high serum IL-15 levels were associated with the effectiveness of this treatment regimen. CAR-19 T cells will likely become an important treatment for patients with relapsed lymphoma.”
The study was supported by the National Cancer Institute (NCI) and NCI Cooperative Research and Development Agreements with Kite Pharma for development of anti-CD19 CAR T-cell therapies.


James N. Kochenderfer, MD, of the Experimental Transplantation and Immunology Branch, NCI, is the corresponding author of the Journal of Clinical Oncology article.

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