A sensitivity scale for targeting t cells with chimeric antigen receptors (CARs) and bispecific t-cell engagers (BiTEs)

Jennifer D. Stone, David H. Aggen, Andrea Schietinger, Hans Schreiber, David M Kranz

Research output: Contribution to journalArticle

Abstract

Although T cells can mediate potent antitumor responses, immune tolerance mechanisms often result in the deletion or inactivation of T cells that express T-cell receptors (TCRs) against potentially effective target epitopes. Various approaches have been devised to circumvent this problem. In one approach, the gene encoding an antibody against a cancerassociated antigen is linked, in the form of a single-chain variable fragment (scFv), to genes that encode transmembrane and signaling domains. This chimeric antigen receptor (CA R) is then introduced into T cells for adoptive T-cell therapy. In another approach, the anti-cancer scFv is fused to a scFv that binds to the CD3e subunit of the TCR/CD3 complex. This fusion protein serves as a soluble, injectable product that has recently been termed bispecific T-cell engager (BiTE). Both strategies have now been tested in clinical trials with promising results, but the comparative efficacies are not known. Here, we performed a direct comparison of the in vitro sensitivity of each strategy, using the same anti-cancer scFv fragments, directed against a tumor-specific glycopeptide epitope on the sialomucin-like transmembrane glycoprotein OTS8, which results form a cancer-specific mutation of Cosmc. While both approaches showed specific responses to the epitope as revealed by T cell-mediated cytokine release and target cell lysis, CA R-targeted T cells were more sensitive than BiTE-targeted T cells to low numbers of antigens per cell. The sensitivity scale described here provides a guide to the potential use of these two different approaches.

Original languageEnglish (US)
Pages (from-to)863-873
Number of pages11
JournalOncoImmunology
Volume1
Issue number6
DOIs
StatePublished - Dec 1 2012

Fingerprint

Antigen Receptors
T-Lymphocytes
T-Cell Antigen Receptor
Epitopes
Neoplasms
Sialomucins
CD3 Antigens
Antigens
Single-Chain Antibodies
Immune Tolerance
Glycopeptides
Cell- and Tissue-Based Therapy
Genes
Glycoproteins
Clinical Trials
Cytokines
Mutation
Injections
Antibodies

Keywords

  • Bispecific T-cell engager (BiTE)
  • Chimeric antigen receptors (CARs)
  • Gene-modified adoptive T-cell transfer
  • T-cell tumor therapy
  • Tumor-specific epitope

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

Cite this

A sensitivity scale for targeting t cells with chimeric antigen receptors (CARs) and bispecific t-cell engagers (BiTEs). / Stone, Jennifer D.; Aggen, David H.; Schietinger, Andrea; Schreiber, Hans; Kranz, David M.

In: OncoImmunology, Vol. 1, No. 6, 01.12.2012, p. 863-873.

Research output: Contribution to journalArticle

Stone, Jennifer D. ; Aggen, David H. ; Schietinger, Andrea ; Schreiber, Hans ; Kranz, David M. / A sensitivity scale for targeting t cells with chimeric antigen receptors (CARs) and bispecific t-cell engagers (BiTEs). In: OncoImmunology. 2012 ; Vol. 1, No. 6. pp. 863-873.
@article{357262c2255943188b97f95b0c09efe8,
title = "A sensitivity scale for targeting t cells with chimeric antigen receptors (CARs) and bispecific t-cell engagers (BiTEs)",
abstract = "Although T cells can mediate potent antitumor responses, immune tolerance mechanisms often result in the deletion or inactivation of T cells that express T-cell receptors (TCRs) against potentially effective target epitopes. Various approaches have been devised to circumvent this problem. In one approach, the gene encoding an antibody against a cancerassociated antigen is linked, in the form of a single-chain variable fragment (scFv), to genes that encode transmembrane and signaling domains. This chimeric antigen receptor (CA R) is then introduced into T cells for adoptive T-cell therapy. In another approach, the anti-cancer scFv is fused to a scFv that binds to the CD3e subunit of the TCR/CD3 complex. This fusion protein serves as a soluble, injectable product that has recently been termed bispecific T-cell engager (BiTE). Both strategies have now been tested in clinical trials with promising results, but the comparative efficacies are not known. Here, we performed a direct comparison of the in vitro sensitivity of each strategy, using the same anti-cancer scFv fragments, directed against a tumor-specific glycopeptide epitope on the sialomucin-like transmembrane glycoprotein OTS8, which results form a cancer-specific mutation of Cosmc. While both approaches showed specific responses to the epitope as revealed by T cell-mediated cytokine release and target cell lysis, CA R-targeted T cells were more sensitive than BiTE-targeted T cells to low numbers of antigens per cell. The sensitivity scale described here provides a guide to the potential use of these two different approaches.",
keywords = "Bispecific T-cell engager (BiTE), Chimeric antigen receptors (CARs), Gene-modified adoptive T-cell transfer, T-cell tumor therapy, Tumor-specific epitope",
author = "Stone, {Jennifer D.} and Aggen, {David H.} and Andrea Schietinger and Hans Schreiber and Kranz, {David M}",
year = "2012",
month = "12",
day = "1",
doi = "10.4161/onci.20592",
language = "English (US)",
volume = "1",
pages = "863--873",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "6",

}

TY - JOUR

T1 - A sensitivity scale for targeting t cells with chimeric antigen receptors (CARs) and bispecific t-cell engagers (BiTEs)

AU - Stone, Jennifer D.

AU - Aggen, David H.

AU - Schietinger, Andrea

AU - Schreiber, Hans

AU - Kranz, David M

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Although T cells can mediate potent antitumor responses, immune tolerance mechanisms often result in the deletion or inactivation of T cells that express T-cell receptors (TCRs) against potentially effective target epitopes. Various approaches have been devised to circumvent this problem. In one approach, the gene encoding an antibody against a cancerassociated antigen is linked, in the form of a single-chain variable fragment (scFv), to genes that encode transmembrane and signaling domains. This chimeric antigen receptor (CA R) is then introduced into T cells for adoptive T-cell therapy. In another approach, the anti-cancer scFv is fused to a scFv that binds to the CD3e subunit of the TCR/CD3 complex. This fusion protein serves as a soluble, injectable product that has recently been termed bispecific T-cell engager (BiTE). Both strategies have now been tested in clinical trials with promising results, but the comparative efficacies are not known. Here, we performed a direct comparison of the in vitro sensitivity of each strategy, using the same anti-cancer scFv fragments, directed against a tumor-specific glycopeptide epitope on the sialomucin-like transmembrane glycoprotein OTS8, which results form a cancer-specific mutation of Cosmc. While both approaches showed specific responses to the epitope as revealed by T cell-mediated cytokine release and target cell lysis, CA R-targeted T cells were more sensitive than BiTE-targeted T cells to low numbers of antigens per cell. The sensitivity scale described here provides a guide to the potential use of these two different approaches.

AB - Although T cells can mediate potent antitumor responses, immune tolerance mechanisms often result in the deletion or inactivation of T cells that express T-cell receptors (TCRs) against potentially effective target epitopes. Various approaches have been devised to circumvent this problem. In one approach, the gene encoding an antibody against a cancerassociated antigen is linked, in the form of a single-chain variable fragment (scFv), to genes that encode transmembrane and signaling domains. This chimeric antigen receptor (CA R) is then introduced into T cells for adoptive T-cell therapy. In another approach, the anti-cancer scFv is fused to a scFv that binds to the CD3e subunit of the TCR/CD3 complex. This fusion protein serves as a soluble, injectable product that has recently been termed bispecific T-cell engager (BiTE). Both strategies have now been tested in clinical trials with promising results, but the comparative efficacies are not known. Here, we performed a direct comparison of the in vitro sensitivity of each strategy, using the same anti-cancer scFv fragments, directed against a tumor-specific glycopeptide epitope on the sialomucin-like transmembrane glycoprotein OTS8, which results form a cancer-specific mutation of Cosmc. While both approaches showed specific responses to the epitope as revealed by T cell-mediated cytokine release and target cell lysis, CA R-targeted T cells were more sensitive than BiTE-targeted T cells to low numbers of antigens per cell. The sensitivity scale described here provides a guide to the potential use of these two different approaches.

KW - Bispecific T-cell engager (BiTE)

KW - Chimeric antigen receptors (CARs)

KW - Gene-modified adoptive T-cell transfer

KW - T-cell tumor therapy

KW - Tumor-specific epitope

UR - http://www.scopus.com/inward/record.url?scp=84878921225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878921225&partnerID=8YFLogxK

U2 - 10.4161/onci.20592

DO - 10.4161/onci.20592

M3 - Article

VL - 1

SP - 863

EP - 873

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 6

ER -