T cells bearing a chimeric antigen receptor against the tumor vasculature destroy the tumor endothelium and result in tumor regression / Stephen Santoro.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Santoro, Stephen, author.

Contributor:

Coukos, George, degree supervisor.

Ryeom, Sandra W., degree committee member.

Powell, Daniel J., Jr., degree committee member.

June, Carl H., degree committee member.

Vonderheide, Robert H., degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

xi, 113 leaves ; 29 cm

Production:

[Philadelphia, Pennsylvania] : [University of Pennsylvania], 2014.

Summary:

Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here I describe the development of two chimeric antigen receptors (CAR)s against the tumor vasculature, targeting either tumor endothelial marker 1 (TEM1) or prostate-specific membrane antigen (PSMA). CAR T cells incorporating scFv78, an scFv isolated against TEM1, were able to recognize immobilized plate-bound TEM1 protein, but were unable to recognize TEM1 on the surface of endothelial cell targets. In contrast, anti-PSMA CAR T cells, which incorporate the J591 scFv, were able to recognize human PSMA (hPSMA) both in vitro and in vivo. To elucidate the role of intracellular signaling domains on endothelial cell killing, a panel of the J591-based CAR T cells was characterized, each harboring a different combination of the intracellular signaling domains, CD3 zeta (ζ), CD28 (28), and CD137/4-1BB (BB). I found that all anti-hPSMA CAR T cells were able to recognize and eliminate PSMA + endothelial targets in vitro, regardless of signaling domain. Furthermore, T cells bearing the 3rd generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecological cancers. In addition, the P28BBζ CAR T cells were able to mediate regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine ovarian cancers models populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA + vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA.

Notes:

Ph. D. University of Pennsylvania 2014.

Department: Cell and Molecular Biology.

Supervisor: George Coukos.

Includes bibliographical references.