CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia
Science Translational Medicine
20 Mar 2013
Vol 5, Issue 177
p. 177ra38
CARving a Niche for Cancer Immunotherapy
Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells that fend off infection. It’s most common in children but—as with many diseases that primarily affect children—has a much worse prognosis when it affects adults. Adults with relapsed disease have a very low chance of survival, and new therapies are desperately needed. Now, Brentjens et al. test T cells engineered to target CD19, which is expressed on both healthy B lymphocytes and B-ALL cells, in five chemotherapy-refractory adult B-ALL patients.
Here, the authors treat patients with the patients’ own T cells altered to express not only CD19 but also a fusion of the costimulatory molecule CD28 with CD3ζ chain—so-called “second-generation chimeric antigen receptor (CAR) T cells.” All patients treated with these cells achieved tumor eradication and complete remission. These CAR T cells were well tolerated, although there was substantial cytokine release in some patients that correlated to tumor burden. These patients were treated with steroid therapy. Long-term follow-up in four of these patients was not possible because the CAR T cell therapy allowed these patients to be eligible for subsequent hematopoietic stem cell transplant (HSCT), which resulted in restored hematopoiesis. The remaining patient experienced a relapse of CD19+ cells that coincided with the lack of persistence of the CAR T cells from circulation. These data suggest that subsequent transfusions should be considered for patients unable to undergo HSCT.
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/CD3ζ 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.
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Supplementary Material
Summary
Fig. S1. Trial schema for adult patients with relapsed B-ALL.
Fig. S2. Trial schema for adult patients with B-ALL in CR.
Fig. S3. Serum cytokine detection and correlation with tumor burden.
Fig. S4. Rapid hematopoietic recovery in MSK-ALL05 after infusion with 19-28z T cells.
Table S1. Characteristics of infused 19-28z CAR-transduced T cells; tumor burden in apheresis and BM.
Table S2. Adverse events.
Table S3. Percentage of 19-28z CAR+ T cells detected in the CD3+ T cells of the peripheral blood and of the BM (in parenthesis) of patients up to 57 days after CAR-modified T cell therapy.
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Published In
Science Translational Medicine
Volume 5 | Issue 177
March 2013
March 2013
Copyright
Copyright © 2013, American Association for the Advancement of Science.
Submission history
Received: 13 February 2013
Accepted: 8 March 2013
Acknowledgments
We thank V. Capacio, J. Hosey, and Y. Wang for excellent technical and quality control assistance. Funding: We thank the following for financial support: the National Cancer Institute (R.J.B., M.L.D., I.R., and M.S.), the American Society of Hematology–Amos Medical Faculty Development Program (M.L.D.), the Alliance for Cancer Gene Therapy (M.S.), the Carson Family Charitable Trust (R.J.B.), the William Lawrence and Blanche Hughes Foundation (R.J.B. and K.C.), the Mallah Foundation, the Majors Foundation and Mr. Lew Sanders (M.S., R.J.B., and I.R.), the Annual Terry Fox Run for Cancer Research (New York, NY) organized by the Canada Club of New York (R.J.B.), Kate’s Team, the CLL Global Research Foundation (R.J.B.), the St. Baldrick’s Foundation (K.C.), and Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Cancer Foundation for Research and the Experimental Therapeutics Center of MSKCC (M.S., R.J.B., and I.R.). Author contributions: M.S., R.J.B., and I.R. conceptualized the overall strategy and developed its clinical translation and implementation. The clinical protocol was written by M.L.D., M.S., and R.J.B. M.L.D. is the principal investigator of the protocol. Manufacturing of T cells, flow cytometry, and quantitative PCR acquisition of clinical samples was performed by C.T., J.S., J.Q., M.O., O.B.-O., Q.H., and T.W., supervised by X.W., and directed by I.R. Data from manufacturing and FACS/quantitative PCR monitoring were analyzed by X.W. and I.R. The manuscript was written by R.J.B., M.S., M.L.D., I.R., and J.P. R.J.B., M.S., I.R., J.P., and X.W. discussed and interpreted the results. L.G.C. performed statistical analyses and analyzed correlation between cytokine levels and tumor burden. R.J.B., M.L.D., J.P., R.K., K.C., P.S., J.J., T.R., and M.F. enrolled patients to the protocol and/or managed the leukemia patients in Memorial Hospital. I.V.R. and C.H. designed and performed molecular assays to identify the malignant IgH clonotype associated with the leukemia cells of enrolled and treated patients. P.M. evaluated all pre- and posttreatment bone marrow aspirates for evidence of leukemia. Y.B. is the Research Study Assistant for the protocol and assisted with enrollment, sample acquisition, and data safety monitoring of patients. Competing interests: M.S. and R.J.B. are co-holders of U.S. Patent 7,446,190, which covers the 19-28z receptor. The other authors declare that they have no competing interests.
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