In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors Journal Article
| Authors: | Khalil, D. N.; Suek, N.; Campesato, L. F.; Budhu, S.; Redmond, D.; Samstein, R. M.; Krishna, C.; Panageas, K. S.; Capanu, M.; Houghton, S.; Hirschhorn, D.; Zappasodi, R.; Giese, R.; Gasmi, B.; Schneider, M.; Gupta, A.; Harding, J. J.; Moral, J. A.; Balachandran, V. P.; Wolchok, J. D.; Merghoub, T. |
| Article Title: | In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors |
| Abstract: | Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while sparing the intervening draining lymph node and spleen. Furthermore, patients with transcription changes like those induced by this therapy experienced improved progression-free survival with anti–PD-1 treatment. Dual CD40-TLR4 activation within a single tumor is thus an approach for overcoming resistance to PD-1 blockade that is unique in its ability to cause the loss of exhausted T cells within tumors while sparing nonmalignant tissues. © 2019, American Society for Clinical Investigation. |
| Keywords: | controlled study; human cell; nonhuman; neoplasm; cd8+ t lymphocyte; animal cell; progression free survival; spleen; tumor regression; cancer model; toll like receptor 4; lymph node; vaccination; tumor cell; antigen presenting cell; lymphoid organ; programmed death 1 receptor; cd40 antigen; human; priority journal; article |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 129 |
| Issue: | 8 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2019-08-01 |
| Start Page: | 3435 |
| End Page: | 3447 |
| Language: | English |
| DOI: | 10.1172/jci128562 |
| PUBMED: | 31329159 |
| PROVIDER: | scopus |
| PMCID: | PMC6668692 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2019 -- Source: Scopus |
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