TY - JOUR
T1 - Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels
AU - Kochenderfer, James N.
AU - Somerville, Robert P.T.
AU - Lu, Tangying
AU - Shi, Victoria
AU - Bot, Adrian
AU - Rossi, John
AU - Xue, Allen
AU - Goff, Stephanie L.
AU - Yang, James C.
AU - Sherry, Richard M.
AU - Klebanoff, Christopher A.
AU - Kammula, Udai S.
AU - Sherman, Marika
AU - Perez, Arianne
AU - Yuan, Constance M.
AU - Feldman, Tatyana
AU - Friedberg, Jonathan W.
AU - Roschewski, Mark J.
AU - Feldman, Steven A.
AU - McIntyre, Lori
AU - Toomey, Mary Ann
AU - Rosenberg, Steven A.
N1 - Funding Information:
Supported by the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, and by NCI Cooperative Research and Development Agreements with Kite Pharma for development of anti-CD19 CAR T-cell therapies (J.N.K. and S.A.R.). We thank the staff of the Surgery Branch of the National Cancer Institute (NCI) cell production facility, Surgery Branch NCI Immunotherapy Fellows, and the staffs of the three Northwest Nursing Units and the Intensive Care Unit of the National Institutes of Health Clinical Center, and the National Gene Vector Biorepository for help monitoring replication-competent retroviruses.
Publisher Copyright:
© 2017 by American Society of Clinical Oncology.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Purpose T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells. Patients and Methods We treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by low-dose chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a low-dose chemotherapy conditioning regimen of cyclophosphamide plus fludarabine. Results The overall remission rate was 73% with 55% complete remissions and 18% partial remissions. Eleven of 12 complete remissions are ongoing. Fifty-five percent of patients had grade 3 or 4 neurologic toxicities that completely resolved. The low-dose chemotherapy conditioning regimen depleted blood lymphocytes and increased serum interleukin-15 (IL-15). Patients who achieved a remission had a median peak blood CAR+ cell level of 98/mL and those who did not achieve a remission had a median peak blood CAR+ cell level of 15/mL (P = .027). High serum IL-15 levels were associated with high peak blood CAR+ cell levels (P = .001) and remissions of lymphoma (P, .001). Conclusion 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.
AB - Purpose T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells. Patients and Methods We treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by low-dose chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a low-dose chemotherapy conditioning regimen of cyclophosphamide plus fludarabine. Results The overall remission rate was 73% with 55% complete remissions and 18% partial remissions. Eleven of 12 complete remissions are ongoing. Fifty-five percent of patients had grade 3 or 4 neurologic toxicities that completely resolved. The low-dose chemotherapy conditioning regimen depleted blood lymphocytes and increased serum interleukin-15 (IL-15). Patients who achieved a remission had a median peak blood CAR+ cell level of 98/mL and those who did not achieve a remission had a median peak blood CAR+ cell level of 15/mL (P = .027). High serum IL-15 levels were associated with high peak blood CAR+ cell levels (P = .001) and remissions of lymphoma (P, .001). Conclusion 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.
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U2 - 10.1200/JCO.2016.71.3024
DO - 10.1200/JCO.2016.71.3024
M3 - Article
C2 - 28291388
AN - SCOPUS:85017643829
SN - 0732-183X
VL - 35
SP - 1803
EP - 1813
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 16
ER -