Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy

Uma Thanarajasingam, Laura Sanz, Rosa Diaz, Jian Qiao, Luis Sanchez-Perez, Tim Kottke, Jill Thompson, John Chester, Richard G. Vile

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.

Original languageEnglish (US)
Pages (from-to)300-308
Number of pages9
JournalCancer Research
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Cell- and Tissue-Based Therapy
T-Lymphocytes
Adoptive Transfer
Neoplasms
Melanoma
Chemokine CCL21
Immunologic Memory
Retroviridae
Clinical Protocols
Chemokines
Adsorption
Immunity
Cell Survival
Therapeutics
Down-Regulation
Observation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Thanarajasingam, U., Sanz, L., Diaz, R., Qiao, J., Sanchez-Perez, L., Kottke, T., ... Vile, R. G. (2007). Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy. Cancer Research, 67(1), 300-308. https://doi.org/10.1158/0008-5472.CAN-06-1017

Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy. / Thanarajasingam, Uma; Sanz, Laura; Diaz, Rosa; Qiao, Jian; Sanchez-Perez, Luis; Kottke, Tim; Thompson, Jill; Chester, John; Vile, Richard G.

In: Cancer Research, Vol. 67, No. 1, 01.01.2007, p. 300-308.

Research output: Contribution to journalArticle

Thanarajasingam, U, Sanz, L, Diaz, R, Qiao, J, Sanchez-Perez, L, Kottke, T, Thompson, J, Chester, J & Vile, RG 2007, 'Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy', Cancer Research, vol. 67, no. 1, pp. 300-308. https://doi.org/10.1158/0008-5472.CAN-06-1017
Thanarajasingam, Uma ; Sanz, Laura ; Diaz, Rosa ; Qiao, Jian ; Sanchez-Perez, Luis ; Kottke, Tim ; Thompson, Jill ; Chester, John ; Vile, Richard G. / Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy. In: Cancer Research. 2007 ; Vol. 67, No. 1. pp. 300-308.
@article{7214473a30634b5a9e12a35da0fbdf15,
title = "Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy",
abstract = "Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.",
author = "Uma Thanarajasingam and Laura Sanz and Rosa Diaz and Jian Qiao and Luis Sanchez-Perez and Tim Kottke and Jill Thompson and John Chester and Vile, {Richard G.}",
year = "2007",
month = "1",
day = "1",
doi = "10.1158/0008-5472.CAN-06-1017",
language = "English (US)",
volume = "67",
pages = "300--308",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy

AU - Thanarajasingam, Uma

AU - Sanz, Laura

AU - Diaz, Rosa

AU - Qiao, Jian

AU - Sanchez-Perez, Luis

AU - Kottke, Tim

AU - Thompson, Jill

AU - Chester, John

AU - Vile, Richard G.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.

AB - Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.

UR - http://www.scopus.com/inward/record.url?scp=33846414710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846414710&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-1017

DO - 10.1158/0008-5472.CAN-06-1017

M3 - Article

C2 - 17210711

AN - SCOPUS:33846414710

VL - 67

SP - 300

EP - 308

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 1

ER -