4.8 Article

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

Journal

CANCER RESEARCH
Volume 67, Issue 1, Pages 300-308

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-1017

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Funding

  1. NCI NIH HHS [1R01 CA 94180, 1R01 CA 107082] Funding Source: Medline
  2. NATIONAL CANCER INSTITUTE [R01CA107082, R01CA094180] Funding Source: NIH RePORTER

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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.

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