Al's Comment:
This is one of my favorite trials now. It is for people with Glioblastoma multiforme who have the EGFR vIII mutation. It can be done at the time of recurrence or for newly diagnosed if they have residual tumor. For details go to: http://virtualtrials.com/Clinical_Trials_Details.cfm?nct=NCT02209376
Posted on: 02/21/2015
Sci Transl Med. 2015 Feb 18;7(275):275ra22.
Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma.
Johnson LA1, Scholler J2, Ohkuri T3, Kosaka A3, Patel PR2, McGettigan SE2, Nace AK4, Dentchev T4, Thekkat P5, Loew A5, Boesteanu AC2, Cogdill AP2, Chen T2, Fraietta JA2, Kloss CC2, Posey AD Jr2, Engels B5, Singh R5, Ezell T5, Idamakanti N5, Ramones MH5, Li N5, Zhou L5, Plesa G2, Seykora JT4, Okada H6, June CH1, Brogdon JL5, Maus MV7.
Author information:
1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
3Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
4Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
5Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
6Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94158, USA.
7Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. marcela.maus@uphs.upenn.edu.
Abstract
Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second-generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII+ glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376).
Copyright © 2015, American Association for the Advancement of Science.
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