Monoclonal TCR-redirected tumor cell killing

Nathaniel Liddy; Giovanna Bossi; Katherine J Adams; Anya Lissina; Tara M Mahon; Namir J Hassan; Jessie Gavarret; Frayne C Bianchi; Nicholas J Pumphrey; Kristin Ladell; Emma Gostick; Andrew K Sewell; Nikolai M Lissin; Naomi E Harwood; Peter E Molloy; Yi Li; Brian J Cameron; Malkit Sami; Emma E Baston; Penio T Todorov; Samantha J Paston; Rebecca E Dennis; Jane V Harper; Steve M Dunn; Rebecca Ashfield; Andy Johnson; Yvonne McGrath; Gabriela Plesa; Carl H June; Michael Kalos; David A Price; Annelise Vuidepot; Daniel D Williams; Deborah H Sutton; Bent K Jakobsen

doi:10.1038/nm.2764

Monoclonal TCR-redirected tumor cell killing

Nathaniel Liddy, Giovanna Bossi, Katherine J Adams, Anya Lissina, Tara M Mahon, Namir J Hassan, Jessie Gavarret, Frayne C Bianchi, Nicholas J Pumphrey, Kristin Ladell, Emma Gostick, Andrew K Sewell, Nikolai M Lissin, Naomi E Harwood, Peter E Molloy, Yi Li, Brian J Cameron, Malkit Sami, Emma E Baston, Penio T TodorovSamantha J Paston, Rebecca E Dennis, Jane V Harper, Steve M Dunn, Rebecca Ashfield, Andy Johnson, Yvonne McGrath, Gabriela Plesa, Carl H June, Michael Kalos, David A Price, Annelise Vuidepot, Daniel D Williams, Deborah H Sutton, Bent K Jakobsen

Bristol Veterinary School

Research output: Contribution to journal › Article (Academic Journal) › peer-review

265 Citations (Scopus)

Abstract

T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.

Original language	English
Pages (from-to)	980-7
Number of pages	8
Journal	Nature Medicine
Volume	18
Issue number	6
DOIs	https://doi.org/10.1038/nm.2764
Publication status	Published - Jun 2012

Keywords

Animals
CD8-Positive T-Lymphocytes
Cytotoxicity, Immunologic
Humans
Immunologic Memory
Immunotherapy
Interferon-gamma
Lymphocyte Activation
Mice
Mice, SCID
Neoplasms, Experimental
Receptors, Antigen, T-Cell

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Liddy, N., Bossi, G., Adams, K. J., Lissina, A., Mahon, T. M., Hassan, N. J., Gavarret, J., Bianchi, F. C., Pumphrey, N. J., Ladell, K., Gostick, E., Sewell, A. K., Lissin, N. M., Harwood, N. E., Molloy, P. E., Li, Y., Cameron, B. J., Sami, M., Baston, E. E., ... Jakobsen, B. K. (2012). Monoclonal TCR-redirected tumor cell killing. Nature Medicine, 18(6), 980-7. https://doi.org/10.1038/nm.2764

@article{97c92976020f4a15b31697107741cc98,

title = "Monoclonal TCR-redirected tumor cell killing",

abstract = "T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.",

keywords = "Animals, CD8-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Humans, Immunologic Memory, Immunotherapy, Interferon-gamma, Lymphocyte Activation, Mice, Mice, SCID, Neoplasms, Experimental, Receptors, Antigen, T-Cell",

author = "Nathaniel Liddy and Giovanna Bossi and Adams, \{Katherine J\} and Anya Lissina and Mahon, \{Tara M\} and Hassan, \{Namir J\} and Jessie Gavarret and Bianchi, \{Frayne C\} and Pumphrey, \{Nicholas J\} and Kristin Ladell and Emma Gostick and Sewell, \{Andrew K\} and Lissin, \{Nikolai M\} and Harwood, \{Naomi E\} and Molloy, \{Peter E\} and Yi Li and Cameron, \{Brian J\} and Malkit Sami and Baston, \{Emma E\} and Todorov, \{Penio T\} and Paston, \{Samantha J\} and Dennis, \{Rebecca E\} and Harper, \{Jane V\} and Dunn, \{Steve M\} and Rebecca Ashfield and Andy Johnson and Yvonne McGrath and Gabriela Plesa and June, \{Carl H\} and Michael Kalos and Price, \{David A\} and Annelise Vuidepot and Williams, \{Daniel D\} and Sutton, \{Deborah H\} and Jakobsen, \{Bent K\}",

year = "2012",

month = jun,

doi = "10.1038/nm.2764",

language = "English",

volume = "18",

pages = "980--7",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "6",

}

Liddy, N, Bossi, G, Adams, KJ, Lissina, A, Mahon, TM, Hassan, NJ, Gavarret, J, Bianchi, FC, Pumphrey, NJ, Ladell, K, Gostick, E, Sewell, AK, Lissin, NM, Harwood, NE, Molloy, PE, Li, Y, Cameron, BJ, Sami, M, Baston, EE, Todorov, PT, Paston, SJ, Dennis, RE, Harper, JV, Dunn, SM, Ashfield, R, Johnson, A, McGrath, Y, Plesa, G, June, CH, Kalos, M, Price, DA, Vuidepot, A, Williams, DD, Sutton, DH & Jakobsen, BK 2012, 'Monoclonal TCR-redirected tumor cell killing', Nature Medicine, vol. 18, no. 6, pp. 980-7. https://doi.org/10.1038/nm.2764

TY - JOUR

T1 - Monoclonal TCR-redirected tumor cell killing

AU - Liddy, Nathaniel

AU - Bossi, Giovanna

AU - Adams, Katherine J

AU - Lissina, Anya

AU - Mahon, Tara M

AU - Hassan, Namir J

AU - Gavarret, Jessie

AU - Bianchi, Frayne C

AU - Pumphrey, Nicholas J

AU - Ladell, Kristin

AU - Gostick, Emma

AU - Sewell, Andrew K

AU - Lissin, Nikolai M

AU - Harwood, Naomi E

AU - Molloy, Peter E

AU - Li, Yi

AU - Cameron, Brian J

AU - Sami, Malkit

AU - Baston, Emma E

AU - Todorov, Penio T

AU - Paston, Samantha J

AU - Dennis, Rebecca E

AU - Harper, Jane V

AU - Dunn, Steve M

AU - Ashfield, Rebecca

AU - Johnson, Andy

AU - McGrath, Yvonne

AU - Plesa, Gabriela

AU - June, Carl H

AU - Kalos, Michael

AU - Price, David A

AU - Vuidepot, Annelise

AU - Williams, Daniel D

AU - Sutton, Deborah H

AU - Jakobsen, Bent K

PY - 2012/6

Y1 - 2012/6

N2 - T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.

AB - T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.

KW - Animals

KW - CD8-Positive T-Lymphocytes

KW - Cytotoxicity, Immunologic

KW - Humans

KW - Immunologic Memory

KW - Immunotherapy

KW - Interferon-gamma

KW - Lymphocyte Activation

KW - Mice

KW - Mice, SCID

KW - Neoplasms, Experimental

KW - Receptors, Antigen, T-Cell

U2 - 10.1038/nm.2764

DO - 10.1038/nm.2764

M3 - Article (Academic Journal)

C2 - 22561687

SN - 1078-8956

VL - 18

SP - 980

EP - 987

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

Monoclonal TCR-redirected tumor cell killing

Abstract

Keywords

UN SDGs

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