T Cells Bearing a Chimeric Antigen Receptor against Prostate-Specific Membrane Antigen Mediate Vascular Disruption and Result in Tumor Regression

Abstract

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 we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA+ endothelial targets in vitro, regardless of the signaling domain. T cells bearing the 3rd generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers 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.

Rational development and characterization of humanized anti–EGFR variant III chimeric antigen receptor T cells for glioblastoma

“…Although most success has resulted from clinical trials targeting CD19 for hematological malignancies (3–5, 43, 44), promising responses have also been observed in solid tumors when targeting NY-ESO-1 on melanoma and synovial cell sarcoma (45). Additional ongoing trials and preclinical studies are targeting PSMA (prostate-specific membrane antigen) for prostate cancers (46), ganglioside G D2 for neuroblastoma (47), mesothelin for lung cancers (30), and others. The greatest impediment to widespread application of CAR T cell therapies remains the selection of appropriate target antigens.…”

A Tet-On Inducible System for Controlling CD19-Chimeric Antigen Receptor Expression upon Drug Administration

“…7). Previously published preclinical studies or clinical trials strongly suggest the possibility that this novel technology may also be applicable to patients with other types of hematologic malignancies such as myeloid leukemia (8), multiple myeloma (9), or certain other types of solid tumors (10)(11)(12). However, because almost no antigens are truly tumor specific, it is necessary to prepare for some degree of adverse events related to CAR T-cell therapy.…”

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“…The protein has a precise structure, defined by the recombinant gene from which it is expressed, which increases its chances of meeting the requirements of clinical development and regulatory approval processes [34]. Our protein vector, dsRB-SCP (dsRB-Arg 9 -ScFvJ591), is a chimeric protein that comprises: (a) a polyIC-binding moiety, consisting of two dsRNA binding domains (dsRBD) derived from human dsRNA-activated protein kinase (PKR); (b) a nine residue arginine linker (Arg 9 ), to facilitate endosomal escape following endocytosis, in accordance with the findings of He et al [35,36]; (c) a specific targeting moiety, consisting of anti-PSMA single-chain antibody, ScFvJ591 [29,37]. We show that dsRB-SCP successfully binds polyIC and elicits a powerful and selective killing effect on PSMAoverexpressing prostate cancer cells.…”