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 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Thanarajasingam, U., Sanz, L., Diaz, R., Qiao, J., Sanchez-Perez, L., Kottke, T., Thompson, J., Chester, J., & 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