title: Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels.
abstract: 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/μL and those who did not achieve a remission had a median peak blood CAR+cell level of 15/μL ( 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.
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: James N
authors.initials: JN
authors.lastname: Kochenderfer
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Robert P T
authors.initials: RPT
authors.lastname: Somerville
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Tangying
authors.initials: T
authors.lastname: Lu
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Victoria
authors.initials: V
authors.lastname: Shi
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bot
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: John
authors.initials: J
authors.lastname: Rossi
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Allen
authors.initials: A
authors.lastname: Xue
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Goff
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Marika
authors.initials: M
authors.lastname: Sherman
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Constance M
authors.initials: CM
authors.lastname: Yuan
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Feldman
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Roschewski
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Lori
authors.initials: L
authors.lastname: McIntyre
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Toomey
authors.affiliation: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019409:Interleukin-15 / Q000097:blood* / Q000276:immunology; D008223:Lymphoma / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019172:Transplantation Conditioning / Q000379:methods; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D018941:Antigens, CD19; C569274:IL15 protein, human; D019409:Interleukin-15; D011948:Receptors, Antigen, T-Cell; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine