Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels

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 - 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.

UR - https://www.scopus.com/pages/publications/85017643829

U2 - 10.1200/JCO.2016.71.3024

DO - 10.1200/JCO.2016.71.3024

M3 - Article

C2 - 28291388

SN - 0732-183X

VL - 35

SP - 1803

EP - 1813

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 16

ER -