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, Timothy, Thompson, Jill, Chester, John D. ORCID: https://orcid.org/0000-0002-7830-3840 and Vile, Richard G. 2007. Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy. Cancer Research 67 (1) , pp. 300-308. 10.1158/0008-5472.CAN-06-1017

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Association for Cancer Research
ISSN:	1538-7445
Funders:	Mayo Foundation, NIH grants 1RO1CA94180 and 1RO1CA107082
Last Modified:	25 Oct 2022 08:21
URI:	https://orca.cardiff.ac.uk/id/eprint/52493

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