T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia

T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia: "Sci Transl Med 10 August 2011:
Vol. 3, Issue 95, p. 95ra73
DOI: 10.1126/scitranslmed.3002842

* Research Article

Leukemia
T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia

1. Michael Kalos1,2,*,
2. Bruce L. Levine1,2,*,
3. David L. Porter1,3,
4. Sharyn Katz4,
5. Stephan A. Grupp5,6,
6. Adam Bagg1,2 and
7. Carl H. June1,2,†

+ Author Affiliations

1. 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
2. 2Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3. 3Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4. 4Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
5. 5Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
6. 6Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

1. ↵†To whom correspondence should be addressed. E-mail: cjune@exchange.upenn.edu

Abstract

Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex–independent approach for the effective treatment of B cell malignancies.
Footnotes

* ↵* These authors contributed equally to this work.
* Citation: M. Kalos, B. L. Levine, D. L. Porter, S. Katz, S. A. Grupp, A. Bagg, C. H. June, T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

* Copyright © 2011, American Association for the Advancement of Science

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