CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia Journal Article

Authors: Brentjens, R. J.; Davila, M. L.; Riviere, I.; Park, J.; Wang, X.; Cowell, L. G.; Bartido, S.; Stefanski, J.; Taylor, C.; Olszewska, M.; Borquez-Ojeda, O.; Qu, J.; Wasielewska, T.; He, Q.; Bernal, Y.; Rijo, I.; Hedvat, C.; Kobos, R.; Curran, K.; Steinherz, P.; Jurcic, J.; Rosenblat, T.; Maslak, P.; Frattini, M.; Sadelain, M.
Article Title: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia
Abstract: Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ΞΆ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD- complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.
Keywords: adult; cancer chemotherapy; clinical article; protein expression; treatment outcome; aged; middle aged; young adult; prednisone; clinical trial; doxorubicin; drug dose reduction; cytarabine; methotrexate; drug megadose; follow up; t lymphocyte; t-lymphocytes; cells, cultured; cancer immunotherapy; etoposide; cyclophosphamide; dexamethasone; steroid; vincristine; acute lymphoblastic leukemia; t lymphocyte receptor; immunoglobulin heavy chain; gene rearrangement; immunotherapy; gamma interferon; leukemia cell; mitoxantrone; interleukin 6; asparaginase; allogeneic hematopoietic stem cell transplantation; cell therapy; precursor cell lymphoblastic leukemia-lymphoma; hematopoiesis; gamma interferon inducible protein 10; cytokine release; leukemia relapse; cd19 antigen; antigens, cd19; interleukin 2 receptor alpha; mercaptopurine; leukemia remission; steroid therapy; inotuzumab ozogamicin
Journal Title: Science Translational Medicine
Volume: 5
Issue: 177
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2013-03-20
Start Page: 177ra38
Language: English
PROVIDER: scopus
PUBMED: 23515080
DOI: 10.1126/scitranslmed.3005930
PMCID: PMC3742551
Notes: --- - "Export Date: 1 May 2013" - ":doi 10.1126/scitranslmed.3005930" - "Source: Scopus"
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MSK Authors
  1. Renier J Brentjens
    195 Brentjens
  2. Cyrus Hedvat
    123 Hedvat
  3. Joseph G Jurcic
    127 Jurcic
  4. Kevin Joseph Curran
    58 Curran
  5. Jae Hong Park
    145 Park
  6. Marco Luis Davila
    23 Davila
  7. Michel W J Sadelain
    456 Sadelain
  8. Isabelle C Riviere
    164 Riviere
  9. Peter Maslak
    167 Maslak
  10. Xiuyan Wang
    65 Wang
  11. Peter G Steinherz
    168 Steinherz
  12. Rachel Kobos
    65 Kobos
  13. Shirley M Bartido
    34 Bartido
  14. Clare Taylor
    16 Taylor
  15. Qing He
    10 He
  16. Yvette J Bernal
    22 Bernal
  17. Ivelise A Rijo
    11 Rijo
  18. Jinrong Qu
    13 Qu