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Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors

Abstract

Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells. Additional patients have subsequently obtained long-term remissions of advanced-stage B-cell malignancies after infusions of anti-CD19 CAR T cells. Long-term eradication of normal CD19+ B cells from patients receiving infusions of anti-CD19 CAR T cells demonstrates the potent antigen-specific activity of these T cells. Some patients treated with anti-CD19 CAR T cells have experienced acute adverse effects, which were associated with increased levels of serum inflammatory cytokines. Although anti-CD19 CAR T cells are at an early stage of development, the potent antigen-specific activity observed in patients suggests that infusions of anti-CD19 CAR T cells might become a standard therapy for some B-cell malignancies.

Key Points

  • T cells can be genetically modified to express chimeric antigen receptors (CARs), which are fusion proteins made up of antigen-recognition moieties and T-cell activation domains

  • CD19 is a suitable target for CAR T cells because it is expressed by B-cell malignancies, but not by normal essential tissues

  • Depleting endogenous lymphocytes by administering chemotherapy or radiotherapy before infusions of adoptively transferred T cells enhances the in vivo activity of the T cells

  • Patients have achieved complete remissions during clinical trials of anti-CD19 CAR T cells; however, acute toxicities associated with elevated serum levels of inflammatory cytokines were noted in trials

  • Evidence for biological activity is provided by long-term depletion of CD19+ normal B cells from several patients receiving infusions of anti-CD19 CAR T cells

  • Adoptive transfer of anti-CD19 CAR T cells is a potent new form of immunotherapy that has the potential to become an important therapy option for some advanced-stage B-cell malignancies

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Figure 1: Chimeric antigen receptors.
Figure 2: Eradication of bone marrow lymphoma and normal B cells occurred after anti-CD19 CAR T cell infusion.
Figure 3: Eradication of bone marrow and blood CLL cells occurred in a patient treated with chemotherapy followed by anti-CD19 CAR T cells and IL-2.
Figure 4: Regression of adenopathy occurred in a patient with CLL after treatment with chemotherapy followed by an infusion of anti-CD19 CAR T cells and IL-2.
Figure 5: A schematic of our current approach to anti-CD19 CAR T cell therapy is shown.

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Acknowledgements

This work was supported by intramural funding of the Center for Cancer Research, National Cancer Institute, NIH, USA.

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Both authors researched data for the article and made a substantial contribution to the discussion of the content. J. N. Kochenderfer wrote the article, and both authors revised and edited it before submission.

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Correspondence to James N. Kochenderfer.

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Kite Pharma has signed a Cooperative Research and Development Agreement with the National Cancer Institute (NCI) to support research in the Surgery Branch, NCI, to develop cell transfer therapies involving the genetic engineering of lymphocytes.

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Kochenderfer, J., Rosenberg, S. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10, 267–276 (2013). https://doi.org/10.1038/nrclinonc.2013.46

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